Valsartan Salts

ABSTRACT

The invention relates to new salts of valsartan or crystalline, also partly crystalline and amorphous salts of valsartan, the respective production and usage, and pharmaceutical preparations containing such a salt.

This application is a continuation application of Ser. No. 10/333,100,filed Feb. 24, 2003, which is a 371 of International Application numberPCT/EP01/08253, filed Jul. 17, 2001.

The invention relates to new salts of the AT₁ receptor antagonist(S)—N-(1-carboxy-2-methyl-prop-1-yl)-N-pentanoyl-N-[2′-(1H-tetrazol-5-yl)-biphenyl-4-yl-methyl]-amine(valsartan) of formula

The active ingredient valsartan is the free acid which is describedspecifically in EP 0443983, especially in example 16; it has two acidichydrogen atoms: (i) the hydrogen atom (H atom) of the carboxyl group,and (ii) that of the tetrazole ring. Accordingly, one acidic H atom(primarily the carboxyl H atom) or both acidic H atoms may be replacedby a monovalent or higher valent, e.g. divalent, cation. Mixed salts mayalso be formed.

EP 443983 does not disclose any specific salts of valsartan. Also, itdoes not mention any special properties of salts. Meanwhile, the activeingredient valsartan has been introduced as an anti-hypertensive agentin a series of countries under the trade name DIOVAN.

The free acid valsartan has a melting point in a closed crucible of 80to 95° C. and in an open crucible of 105 to 110° C. and a meltingenthalpy of 12 kJ/mol. The optical rotation is [α]²⁰ _(D)=(−70±2)° for aconcentration of c=1% in methanol.

The density of the valsartan crystals and of the salt hydrates wasdetermined by a helium pycnometer (Accupyc 1330 of Micromeritics,Norcross, Ga., USA). The density for the crystals of the free acidvalsartan is 1.20±0.02.

The X-ray diffraction diagram consists essentially of a very broad,diffuse Xray reflection; the free acid is therefore characterised asalmost amorphous under X-ray. The melting point linked with the measuredmelting enthalpy of 12 kJ/mol unequivocally confirm the existence of aconsiderable residual arrangement in the particles or structural domainsfor the free acid valsartan.

There is a need for more stable, e.g. crystalline forms of valsartan,which are even easier to manage in the drying or grinding processesfollowing the final stage of the chemical preparation process and alsoin the steps for preparing the pharmaceutical formulations. Many futileattempts have been made to find improved forms through salt formation,the forms ideally being as crystalline as possible, as well asphysically and chemically stable. Only the salts according to theinvention, their solvates and polymorphous forms thereof exhibit thedesired improved properties.

The formation of salts of valsartan with the desired advantageousproperties has proved to be difficult. In the majority of cases, forexample, amorphous salts with little stability are obtained (such ashard foams, waxes or oils). Extensive research has shown that the saltsof valsartan according to the invention have proved to be particularlyadvantageous compared with the free acid valsartan.

The objects of the present invention are salts of valsartan which areselected from the group consisting of the monosodium salt, themonopotassium salt, the dipotassium salt, the magnesium salt, thecalcium salt, the bis-diethylammonium salt, the bis-dipropylammoniumsalt, the bis-dibutylammonium salt, the mono-L-arginine salt, thebis-L-arginine salt, the mono-L-lysine salt and the bis-L-lysine salt,as well as salt mixtures, or respectively, an amorphous form, a solvate,especially hydrate, as well as a polymorphous form thereof, therespective production and usage, and pharmaceutical preparationscontaining such salts.

The objects of the present invention are salts of valsartan which areselected from the group consisting of the monosodium salt, themonopotassium salt, the dipotassium salt, the magnesium salt, thecalcium salt, the bis-diethylammonium salt, the bis-dipropylammoniumsalt, the bis-dibutylammoniumsalt, the mono-L-arginine salt, thebis-L-arginine salt, the mono-L-lysine salt and the bis-L-lysine salt,or respectively, an amorphous form, a solvate, especially hydrate, aswell as a polymorphous form thereof.

Salt mixtures are (i) single salt forms from different cations selectedfrom the above group or (ii) mixtures of those single salt forms whichexist for example in the form of conglomerates.

Preferred salts are for example selected from the

mono-sodium salt in amorphous form;

di-sodium salt of valsartan in amorphous or crystalline form, especiallyin hydrate form, thereof.

Mono-potassium salt of valsartan in amorphous form;

di-potassium salt of valsartan in amorphous or crystalline form,especially in hydrate form, thereof.

calcium salt of valsartan in crystalline form, especially in hydrateform, primarily the tetrahydrate thereof;

magnesium salt of valsartan in crystalline form, especially in hydrateform, primarily the hexahydrate thereof;

calcium/magnesium mixed salt of valsartan in crystalline form,especially in hydrate form;

bis-diethylammonium salt of valsartan in crystalline form, especially inhydrate form;

bis-dipropylammonium salt of valsartan in crystalline form, especiallyin hydrate form;

bis-dibutylammonium salt of valsartan in crystalline form, especially inhydrate form, primarily the hemihydrate thereof;

mono-L-arginine salt of valsartan in amorphous form;

bis-L-arginine salt of valsartan in amorphous form;

mono-L-lysine salt of valsartan in amorphous form;

bis-L-lysine salt of valsartan in amorphous form.

The salts according to the invention preferably exist in isolated andessentially pure form, for example in a degree of purity of >95%,preferably >98%, primarily >99%. The enantiomer purity of the saltsaccording to the invention is >98%, preferably >99%.

Compared with the free acid, the salts according to the invention, orthe amorphous forms, solvates such as salt hydrates, and also thecorresponding polymorphous forms thereof, have unexpectedly advantageousproperties. Under given conditions, the crystalline salts andcrystalline salt hydrates have a clear melting point which is linkedwith a marked, endothermic melting enthalpy. The crystalline saltsaccording to the invention are stable and are of better quality thanvalsartan also during storage and distribution. The amorphous orpartially amorphous salts have limited stability, i.e. as the solid,they have a restricted stability range. To be stabilised, they requirecertain measures which can be achieved for example by galenicformulations.

In addition, both the crystalline and the amorphous salts according tothe invention have a high degree of dissociation in water and thussubstantially improved water solubility. These properties are ofadvantage, since on the one hand the dissolving process is quicker andon the other hand a smaller amount of water is required for suchsolutions. Furthermore, the higher water solubility can, under certainconditions, also lead to increased biological availability of the saltsor salt hydrates in the case of solid dosage forms. Improved propertiesare beneficial especially to the patients. Furthermore, some of thesalts according to the invention have proved to be exceptionallyphysically stable, particularly the alkaline earth salts. For differentrelative humidities at room temperature and also at a slightly highertemperatures, the salt hydrates according to the invention showpractically no water absorption or water loss over a wide range ofhumidities and for periods of a few hours, e.g. four hours. Also, forexample, the melting point of the salts according to the invention willnot be changed by storing under different relative humidities.

Improved physicochemical properties of certain salts or certain salthydrates are of great importance both when they are produced as apharmaceutically active substance and when producing, storing andapplying the galenic preparation. In this way, starting with improvedconstancy of the physical parameters, an even higher quality of theformulations can be guaranteed. The high stability of the salts or salthydrates also give the possibility of attaining economic advantages byenabling simpler process steps to be carried out during working up. Thehigh crystallinity of certain salt hydrates allows the use of a choiceof analytical methods, especially the various X-ray methods, the usageof which permits a clear and simple analysis of their release to bemade. This factor is also of great importance to the quality of theactive substance and its galenic forms during production, storage andadministration to the patients. In addition, complex provisions forstabilising the active ingredient in the galenic formulations can beavoided.

The invention accordingly relates to crystalline, also partlycrystalline and amorphous salts of valsartan.

As well as the solvates, such as hydrates, the invention also relates topolymorphous forms of the salts according to the invention.

Solvates and also hydrates of the salts according to the invention maybe present, for example, as hemi-, mono-, di-, tri-, tetra-, penta-,hexa-solvates or hydrates, respectively. Solvents used forcrystallisation, such as alcohols, especially methanol, ethanol,aldehydes, ketones, especially acetone, esters, e.g. ethyl acetate, maybe embedded in the crystal grating. The extent to which a selectedsolvent or water leads to a solvate or hydrate in crystallisation and inthe subsequent process steps or leads directly to the free acid isgenerally unpredictable and depends on the combinations of processconditions and the various interactions between valsartan and theselected solvent, especially water. The respective stability of theresulting crystalline or amorphous solids in the form of salts, solvatesand hydrates, as well as the corresponding salt solvates or salthydrates, must be determined by experimentation. It is thus not possibleto focus solely on the chemical composition and the stoichiometric ratioof the molecules in the resulting solid, since under these circumstancesboth differing crystalline solids and differing amorphous substances maybe produced.

The description salt hydrates for corresponding hydrates may bepreferred, as water molecules in the crystal structure are bound bystrong intermolecular forces and thereby represent an essential elementof structure formation of these crystals which, in part, areextraordinarily stable. However, water molecules are also existing incertain crystal lattices which are bound by rather weak intermolecularforces. Such molecules are more or less integrated in the crystalstructure forming, but to a lower energetic effect. The water content inamorphous solids can, in general, be clearly determined, as incrystalline hydrates, but is heavily dependent on the drying and ambientconditions. In contrast, in the case of stable hydrates, there are clearstoichiometric ratios between the pharmaceutical active substance andthe water. In many cases these ratios do not fulfil completely thestoichiometric value, normally it is approached by lower values comparedto theory because of certain crystal defects. The ratio of organicmolecules to water molecules for the weaker bound water may vary to aconsiderable extend, for example, extending over di-, tri- ortetra-hydrates. On the other hand, in amorphous solids, the molecularstructure classification of water is not stoichiometric; theclassification may however also be stoichiometric only by chance.

In some cases, it is not possible to classify the exact stoichiometry ofthe water molecules, since layer structures form, e.g. in the alkalimetal salts, especially in the potassium salt, so that the embeddedwater molecules cannot be determined in defined form.

For the crystalline solids having identical chemical composition, thedifferent resulting crystal gratings are summarised by the termpolymorphism.

Any reference hereinbefore and hereinafter, to the salts according tothe invention is to be understood as referring also to the correspondingsolvates, such as hydrates, and polymorphous modifications, and alsoamorphous forms, as appropriate and expedient.

Especially preferred are the tetrahydrate of the calcium salt ofvalsartan and the hexahydrate of the magnesium salt of valsartan.

The X-ray diffraction diagram of powders of these two salt hydrates hasa number of discrete X-ray reflections, and practically no signs ofnon-crystalline or amorphous portions. The degree of crystallisation ofthese defined salt hydrates is therefore surprisingly high. Equally,relatively large crystals may be cultured from certain salt hydrates,and in the crystallographic sense these are single crystals. Such singlecrystals allow the structure of the solid to be determined. It iseffected by computer-aided evaluation of the reflection intensitiesmeasured by an X-ray diffractometer.

This process for determining the structure of a crystal enables, undernormal conditions such as high physical, chemical and enantiomericpurity of the gauged crystals, a clear determination of the structure tobe carried out on a molecular or atomic level, namely symmetry and sizeof the elementary cells, atom positions and temperature factors, andfrom the ascertained cell volume, the X-ray-photographic density isshown on the basis of a molecular weight. At the same time, theX-ray-photographic structure determination supplies details of itsquality.

The outstanding properties of these two salt hydrates are based on thecrystals, which form these salts by incorporating four or six watermolecules per valsartan molecule. Thus, practically perfectthree-dimensional crystal gratings are produced. These two salts havewater solubility that is several times better than the free acid ofvalsartan, and this is especially surprisingly at high melting pointsand melting enthalpies, which are eight or five times greater than thefree acid. The extraordinary crystal gratings of these two salt hydratesare the basis for the chemical and physical stability of these twocompounds.

The particularly notable salt hydrate is the tetrahydrate of the calciumsalt of valsartan. In a closed specimen container, for a heating rate ofT_(r)=10 K·min⁻¹ it has a melting point of 205±1.5° C. and a meltingenthalpy of 98±4 kJ·Mol⁻¹. The tetrahydrate of the calcium salt ofvalsartan is not stable at elevated temperatures both in respect of thehydrate water and in respect of the structure of the molecule. Theindicated melting point is a hydrate melting point which can only bemeasured in a closed specimen container. Gold containers with a wallthickness of 0.2 mm were used; after weighing in samples of between 2and 4 mg salt hydrate, they were sealed by cold welding. These goldcontainers have an internal free volume of ca. 22 microlitres. Theamounts of the sample and the volume of the pressurised containers mustbe suitably adapted, so that strong dehydration of the salt hydratescannot take place during measurement of the melting point. The partialpressure of the water at 205° Celsius is ca. 18 bar, so that with anopen container in DSC (Differential Scanning Calorimeter) duringmeasurement of the melting point, conversion to the anhydrate takesplace. If the data from several heating rates (T_(r)=10, 20, 40 K·min⁻¹)are extrapolated to a continuously rapid heating rate, a melting pointof 213±2° C. and a melting enthalpy of 124±5 kJ·Mol⁻¹ result. Both thehigh hydrate melting point and the amount of the melting enthalpy are anexpression of the exceptional stability of the crystal grating of thetetrahydrate of the calcium salt of valsartan. These two thermodynamiccharacteristics illustrate the advantageous physical properties,compared to the free acid, with the two corresponding data, namely amelting point in the closed system of 90° C. and a melting enthalpy of12 kJ·Mol⁻¹. These thermodynamic data, together with the X-ray data,prove the high stability of this crystal grating. They are thefoundation for the special physical and chemical resistance of thetetrahydrate of the calcium salt of valsartan.

A measurement of the infrared absorption spectrum of the tetrahydrate ofthe calcium salt of valsartan in a potassium bromide compressed tabletshows the following significant bands expressed in reciprocal wavenumbers (cm⁻¹): 3750-3000 (st); 3400-2500 (st); 1800-1520 (st);1500-1380 (st); 1380-1310 (m); 1290-1220 (w); 1220-1190 (w); 1190-1160(w); 1160-1120 (w); 1120-1050 (w); 1030-990 (m); 989-960 (w), 950-920(w); 780-715 (m); 710-470 (m). The intensities of the absorption bandsare indicated as follows: (w)=weak; (m)=medium; and (st)=strongintensity. Measurement of the infrared spectrum likewise took place bymeans of ATR-IR (Attenuated Total Reflection-infrared Spectroscopy)using the instrument Spektrum BX from Perkin-Elmer Corp., Beaconsfield,Bucks, England.

The tetrahydrate of the calcium salt of valsartan has the followingabsorption bands expressed in reciprocal wave numbers (cm⁻¹):

3594 (w); 3306 (w); 3054 (w); 2953 (w); 2870 (w); 1621 (st); 1578 (m);1458 (m); 1441 (m) 1417 (m); 1364 (m); 1336 (w); 1319 (w); 1274 (w);1241 (w); 1211 (w); 1180 (w); 1149 (w); 1137 (w); 1106 (w); 1099 (w);1012 (m); 1002 (w); 974 (w); 966 (w); 955 (w); 941 (w); 863 (w); 855(w); 844 (w); 824 (w); 791 (w); 784 (w); 758 (m); 738 (m); 696 (m); 666(m).

The intensities of the absorption bands are indicated as follows:(w)=weak; (m)=medium and (st)=strong intensity.

The most intensive absorption bands of the ATR-IR spectroscopy are shownby the following values expressed in reciprocal wave numbers (cm⁻¹):3306 (w); 1621 (st); 1578 (m); 1458 (m); 1441 (m); 1417 (m); 1364 (m);1319 (w); 1274 (w); 1211 (w); 1180 (w); 1137 (w); 1012 (m); 1002 (w);758 (m); 738 (m); 696 (m); 666 (m).

The error margin for all absorption bands of ATR-IR is ±2 cm⁻¹.

The water content is in theory 13.2% for the tetrahydrate of the calciumsalt of valsartan. Using the thermo-scale TGS-2 (Perkin-Elmer Corp.,Norwalk, Conn. USA ) the water content was determined as 12.9%. A totalformula was calculated from this (C₂₄H₂₇N₅O₃)^(’−) Ca²⁺. (3.9±0.1) H₂O.

Using thermogravimetry, in a water-free N₂ atmosphere, the weight loss,i.e. the water loss for the tetrahydrate as a function of temperature,was measured at a heating rate of 10 K·min⁻¹. The results areillustrated in table 1. TABLE 1 temperature [° C.] weight loss or waterloss in % 25 0 50 0 75 0.5 100 3.5 125 10.2 150 12.4 175 12.8 200 12.9225 12.9 250 13.0 275 13.2

The solubility of the tetrahydrate of the calcium salt of valsartan inwater-ethanol mixtures is illustrated in Table 2 for a temperature of22° C. TABLE 2 solubility of the tetrahydrate vol-% ethanol of thecalcium salt of valsartan in water in g/l solution at 22° C. 0 9 (pH =7.4) 10  9 30 14 50 46

A comparison of the solubilities of the two most important saltsaccording to the invention and the free acid in distilled water isillustrated in Table 3. TABLE 3 solubility in g/l solution Compound at22° C. valsartan 0.17 tetrahydrate of the calcium salt of valsartan 9hexahydrate of the magnesium salt of 59 valsartan

Further characterisation of the tetrahydrate of the calcium salt ofvalsartan is effected using the interlattice plane intervals determinedby a X-ray powder pattern. Measurement of the X-ray powder patterns wasmade with a Guinier camera (FR 552 from Enraf Nonius, Delft, NL) on anX-ray film in transmission geometry, using Cu-Ka₁ radiation at roomtemperature. Evaluation of the films for calculation of the interlatticeplane intervals is made both visually and by a Line-Scanner (JohanssonTäby, S), and the reflection intensities are determined simultaneously.

The preferred characterisation of the tetrahydrate of the calcium saltof valsartan is obtained from the interlattice plane intervals d of theascertained X-ray diffraction diagrams, whereby, in the following,average values are indicated with the appropriate error limits.

d in [Å]: 16.1±0.3, 9.9±0.2, 9.4±0.2, 8.03±0.1, 7.71±0.1, 7.03±0.1,6.50±0.1, 6.33±0.1, 6.20±0.05, 5.87±0.05, 5.74±0.05, 5.67±0.05,5.20±0.05, 5.05±0.05, 4.95±0.05, 4.73±0.05, 4.55±0.05, 4.33±0.05,4.15±0.05, 4.12±0.05, 3.95±0.05, 3.91±0.05, 3.87±0.05, 3.35±0.05.

The most intensive reflections in the X-ray diffraction diagram show thefollowing interlattice plane intervals:

d in [Å]: 16.1±0.3, 9.9±0.2, 9.4±0.2, 7.03±0.1, 6.50±0.1, 5.87±0.05,5.74±0.05, 4.95±0.05, 4.73±0.05, 4.33±0.05, 4.15±0.05, 4.12±0.05,3.95±0.05.

A preferred method of checking the above-indicated average values of theinterlattice plane intervals and intensities measured by experimentationfrom X-ray diffraction diagrams with a Guinier camera, for a givensubstance, consists in calculating these intervals and their intensitiesfrom the comprehensive single crystal structure determination. Thisstructure determination yields cell constants and atom positions, whichenable the X-ray diffraction diagram corresponding to the solid to becalculated by means of computer-aided calculation methods (programmeCaRine Crystallography, Université de Compiègne, France). A comparisonof these data, namely the interlattice plane intervals and intensitiesof the most important lines of the tetrahydrate of the calcium salt ofvalsartan, obtained from measurements with the Guinier camera and fromcalculating the single crystal data, is illustrated in Table 4. TABLE 4measured calculated d in [Å] Intensity d in [Å] Intensity 16.10 very16.02 very strong strong 9.89 strong 9.88 very strong 9.38 average 9.37average 8.03 weak 8.02 average 7.71 weak 7.70 weak 7.03 average 7.01average 6.50 average 6.49 average 6.33 weak 6.33 weak 6.20 very weak6.19 very weak 5.87 average 5.862 average 5.74 average 5.738 average5.67 very weak 5.658 very weak 5.20 very weak 5.199 very weak 5.05 veryweak 5.040 very weak 4.95 average 4.943 weak 4.73 weak 4.724 weak 4.55weak 4.539 weak 4.33 weak 4.338 weak 4.15 strong 4.150 strong 4.12 weak4.114 weak 3.95 average 3.941 average 3.35 weak 3.349 weak

The invention relates to the crystalline tetrahydrate of the calciumsalt of(S)—N-(1-carboxy-2-methylprop-1-yl)-N-pentanoyl-N-[2′-(1H-tetrazol-5-yl)biphenyl-4-ylmethyl]-amine,a crystalline solid which is clearly characterised by the data andparameters obtained from single crystal X-ray analysis and X-ray powderpatterns. An in-depth discussion of the theory of the methods of singlecrystal X-ray diffraction and the definition of the evaluated crystaldata and the parameters may be found in Stout & Jensen, X-Ray StructureDetermination: A Practical Guide, Mac Millian Co., New York, N.Y. (1968)chapter 3.

The data and parameters of the single crystal X-ray structuredetermination for the tetrahydrate of the calcium salt of valsartan arecontained in Table 5. TABLE 5 Crystal data and parameters of thetetrahydrate of the calcium salt of valsartan Crystal data sum formula(C₂₄H₂₇N₅O₃)²⁻Ca²⁺•4 H₂O molecular mass 545.65 crystal colour colourlesscrystal shape flat prisms crystal system monoclinic space group P2₁ sizeof the single crystal 0.42 · 0.39 · 0.17 mm³ dimensions and angle ofelementary cell a = 10.127(2) Å b = 8.596(2) Å c = 32.214(6) Å α = 90° β= 95.34(3)° γ = 90° volume of elementary cell V_(c) = 2792.1(10) Å³number of molecules in the 4 elementary cell F (000) 1160 measurementrange of cell parameters (Θ) 7.47-16.50° calculated density 1.298 (g ·cm⁻³) linear absorption coefficient 0.274 mm⁻¹ X-ray measurement datadiffractometer Enraf Nonius CAD4 X-radiation (graphite monochromator)MoKα wavelength 0.71073 temperature 295 K scan range (θ) 1.27-31.99°scan mode ω/2 Θ reflections collected/unique 19384/18562 number ofsignificant reflections 10268 (I > 2σ(I)) variation in intensity 1.7%absorption correction numeric Structure refinement method full matrix,least squares, F² number of parameters 893 agreement index (R) 6.2%weighted agreement index (R_(w)) 14.4% S factor (Goodness of fit) 1.085number of reflections used 18562 treatment of all hydrogen atoms in allfound by difference- the molecule, including in the Fourier calculation,almost water molecules all isotropically refined, a few theoreticallyfixed (riding) extinction correction none maximum/minimum residualelectron 0.662/−0.495 (e · Å⁻³) density in conclusive difference-Fourier calculation absolute structure parameters 0.00 (4) Computerprogrammes used SHELXS 86 (Sheldrick, Göttingen, 1990) SHELXL 96(Sheldrick, Göttingen, 1996) SCHAKAL 86 (Keller, Freiburg 1986) PLATON(Spek, Acta Cryst., 1990)

The elementary cell is defined by six parameters, namely by the gratingconstants a, b and c, and by the axial angle, namely by a, β, und γ. Inthis way, the volume of the elementary cell V_(c) is determined. Adifferentiated description of these crystal parameters is illustrated inchapter 3 of Stout & Jensen (see above). The details for thetetrahydrate of the calcium salt of valsartan from the single crystalmeasurements, especially the atom coordinates, the isotropic thermalparameters, the coordinates of the hydrogen atoms as well as thecorresponding isotropic thermal parameters, show that a monoclinicelementary cell exists, its cell content of four formula units Ca²⁺valsartan²⁻.4 H₂O occurring as a result of two crystallographicindependent units on two-fold positions.

Given the acentric space group P2₁ determined from the single crystalX-ray structure determination, a racemate is ruled out. Thus theenantiomeric purity of the S-configuration for the crystallinetetrahydrate of the calcium salt of(S)—N-(1-carboxy-2-methylprop-1-yl)-N-pentanoyl-N-[2′-(1H-tetrazol-5-yl)biphenyl-4-ylmethyl]-amineis verified.

An essential feature for the quality of a pure active substance both forthe physical-chemical procedures such as drying, sieving, grinding, andin the galenic processes which are carried out with pharmaceuticalexcipients, namely in mixing processes, in granulation, in spray-drying,in tabletting, is the water absorption or water loss of this activesubstance depending on temperature and the relative humidity of theenvironment in question. With certain formulations, free and bound wateris without doubt introduced with excipients and/or water is added to theprocess mass for reasons associated with the respective formulationprocess. In this way, the pharmaceutical active substance is exposed tofree water over rather long periods of time, depending on thetemperature of the different activity (partial vapour pressure).

A clear characterisation of this property is achieved by means ofisothermal measurements over predetermined time intervals andpredetermined relative humidity using dynamic vapour sorption (DVS-1from the company Surface Measurement Systems LTD, Marlow,Buckinghamshire, UK). Table 6 illustrates the mass change, i.e. thewater absorption or loss as a function of relative humidity at 25° C.for a sample of 9.5 mg of the tetrahydrate of the calcium salt ofvalsartan and for a period of 4 hours. The following cycles of changesin relative humidity are shown: 40-90; 90-0; 0-90; 90-0 % relativehumidity: TABLE 6 relative relative water humidity water absorptionhumidity absorption or in % or loss in % in % Abgabe in % 40 0.04 100.00 50 0.04 0 −0.01 60 0.03 10 0.00 70 0.02 20 0.00 80 0.02 30 0.00 900.00 40 0.00 80 0.02 50 0.00 70 0.02 60 0.01 60 0.02 70 0.00 50 0.02 80−0.01 40 0.02 90 −0.02 30 0.01 0 −0.02 20 0.01 (starting value) 0.00

The measurement error of this sorption method based on thermogravimetryis about 0.1%. Therefore, the tetrahydrate of the calcium salt ofvalsartan under the conditions employed, which are realistic from apharmaceutical-galenic point of view, shows no measurable waterabsorption or loss. This is surprising to a large extent, since thetetrahydrate, which has incorporated about 13% of bound water in thecrystal structure, is totally indifferent to water even at extremevalues of relative humidity. This property is crucial in the finalstages of chemical manufacture and also in practice in all galenicprocess stages of the different dosage forms. This exceptional stabilitysimilarly benefits the patients through the constant availability of theactive ingredient.

The intrinsic dissolving rates of the calcium salt of valsartan at pH 1,pH 4.5 and pH 6.8 show improved values over those of valsartan.

The exceptional stability of the calcium salt of valsartan, especiallythe tetrahydrate thereof, towards water may also be shown in stabilitytests. In these, the water content of the tetrahydrate of the calciumsalt of valsartan remains constant both in an open container and in asealed ampoule after four weeks at 40° C. and 75% relative humidity.

Owing to the advantageous crystallinity of the calcium salt, especiallythe tetrahydrate thereof, this salt is suitable for pressing directly toform corresponding tablet formulations.

In addition, an improved dissolving profile in a tablet can be assured.In studies of the dissolving profile, it was established that thecalcium salt, especially the tetrahydrate thereof, is released by 100%from a film-coated tablet within 15 minutes.

Of the group of new-type crystalline solids, a magnesium salt hydrate ofvalsartan is preferred, in particular the hexahydrate. The thermalbehaviour of this salt hydrate in the region of the melting point showsa certain chemical and physical instability. The thermal data are thusdependent on the measurement conditions. In the sealed gold specimencontainer with an internal free volume of ca. 22 microlitres, with asample of 2 to 4 mg and with a heating rate of T_(r)=10 K·min⁻¹, themelting point of the hexahydrate of the magnesium salt of valsarten is132±1.5° Celsius and the melting enthalpy is 56±3 kJ·Mol⁻¹. The meltingenthalpy which is about 5 times higher than the free acid of valsartan,together with the significantly higher melting point of the hexahydrateof the magnesium salt of valsartan is a measure of the stability of thenew-type crystal grating at around room temperature.

The optical rotation of the hexahydrate of the magnesium salt ofvalsartan in methanol as a 1% solution at 20° C. is [α]²⁰ _(D)=−14°.

A measurement of the infrared absorption spectrum of the hexahydrate ofthe magnesium salt of valsartan in a potassium bromide compressed tabletshows the following significant bands expressed in reciprocal wavenumbers (cm⁻¹): 3800-3000 (st); 3000-2500 (st); 1800-1500 (st);1500-1440 (m); 1440-1300 (m); 1280-1240 (w); 1240-1190 (w); 1190-1150(w); 1120-1070 (w); 1050-990 (w); 990-960 (w); 960-920 (w); 920-700 (m);700-590 (w); 590-550 (w).

The intensities of the absorption bands are indicated as follows:(w)=weak; (m)=medium; and (st)=strong intensity.

Measurement of the infrared spectrum likewise took place by means ofATR-IR (Attenuated Total Reflection-Infrared Spectroscopy) using theinstrument Spektrum BX from Perkin-Elmer Corp., Beaconsfield, Bucks,England.

The hexahydrate of the magnesium salt of valsartan has the followingabsorption bands expressed in reciprocal wave numbers (cm⁻¹):

3378 (m); 3274 (m); 2956 (m); 2871 (w); 2357 (w); 1684 (w); 1619 (St);1557 (m); 1464 (m); 1419 (m); 1394 (st); 1374 (m); 1339 (w); 1319 (w);1300 (w); 1288 (w); 1271 (w) 1255 (w); 1223 (w); 1210 (w); 1175 (m);1140 (w); 1106 (w); 1047 (w); 1024 (w); 1015 (w); 1005 (w); 989 (w); 975(w); 955 (w); 941 (w); 888 (w); 856 (w); 836 (m); 820 (w); 766 (st); 751(m); 741 (st); 732 (st).

The intensities of the absorption bands are indicated as follows:(w)=weak; (m)=medium and (st)=strong intensity.

The most intensive absorption bands of the ATR-IR spectroscopy are shownby the following values expressed in reciprocal wave numbers (cm⁻¹):3378 (m); 3274 (m); 2956 (m); 1619 (st); 1557 (m); 1464 (m); 1419 (m);1394 (st); 1271 (w); 1175 (m); 1015 (w); 975 (w); 836 (m); 766 (st); 751(m); 741 (st); 732 (st).

The error margin for all absorption bands of ATR-IR is ±2 cm⁻¹.

The theoretical water content of the hexahydrate of the magnesium saltof valsartan is 19.1%. Using a coupled instrument based onthermogravimetry-Fourier transformation-infrared-spectroscopy (TG-FTIR,IFS 28 from the companies Netzsch Gerätebau GmbH, Selb, Bayern andBruker Optik GmbH, Karlsruhe), whilst simultaneously measuring theweight loss and identifying the material component given up, usinginfrared spectroscopy (release of water), the water content wasdetermined at 18.5%, conforming well with the theoretical value. For thehexahydrate, this corresponds to a molar ratio of 5.8±0.2 mols H₂O permol magnesium salt.

Table 7 illustrates the water loss of the hexahydrate of the magnesiumsalt of valsartan depending on temperature, using the weight lossmeasured in an N₂ atmosphere on a thermogravimetric thermal analysisinstrument for a heating rate of 10 K° min⁻¹. From the TG-FTIRmeasurement, the correlation of the weight loss is assured solely by therelease of water. TABLE 7 weight loss or temperature [° C.] waterrelease in % 25 0 50 1.2 75 4.2 100 11.0 125 16.7 150 17.7 175 18.3 20018.5 225 18.7 250 18.9 275 19.3

The hexahydrate of the magnesium salt of valsartan has a solubility indistilled water at 22° C. of 59 g per litre of solution for a pH valueof 9.3.

The crystalline form of the hexahydrate of the magnesium salt ofvalsartan is clearly characterised by the interlattice plane intervalscalculated from the lines in an X-ray powder pattern. The measurementand analysis methods used are the same as those used for thetetrahydrate of the calcium salt of valsartan.

This preferred characterisation of the hexahydrate of the magnesium saltof valsartan is obtained from the interlattice plane intervals d,whereby, in the following, average values are indicated with theappropriate error limits:

d in [Å]: 19.7±0.3, 10.1±0.2, 9.8±0.2, 7.28±0.1, 6.48±0.1, 6.00±0.1,5.81±0.1, 5.68±0.1, 5.40±0.05, 5.22±0.05, 5.12±0.05, 5.03±0.05,4.88±0.05, 4.33±0.05, 4.22±0.05, 4.18±0.05, 4.08±0.05, 3.95±0.05,3.46±0.05, 3.42±0.05.

The most intensive reflections in the X-ray diffraction diagram show thefollowing interlattice plane intervals:

d in [Å]: 19.7±0.3, 10.11±0.2, 9.8±0.2, 7.28±0.1, 5.81±0.05, 5.68±0.05,5.03±0.05, 4.88±0.05, 4.18±0.05, 4.08±0.05, 3.46±0.05.

A preferred method of checking the above-indicated average values of theinterlattice plane intervals and intensities measured by experimentationfrom X-ray diffraction diagrams with a Guinier camera, for a givensubstance, consists in calculating these intervals and their intensitiesfrom the comprehensive single crystal structure determination. Thisstructure determination yields cell constants and atom positions, whichenable the X-ray diffraction diagram corresponding to the solid to becalculated by means of computer-aided calculation methods (programmeCaRine Crystallography, Université de Compiègne, France). A comparisonof these data, namely the interlattice plane intervals and intensitiesof the most important lines of the hexahydrate of the magnesium salt ofvalsartan, obtained from measurements with the Guinier camera and fromcalculating the single crystal data, is illustrated in Table 8. TABLE 8measured calculated d in [Å] Intensity d in [Å] Intensity 19.7 verystrong 19.66 very strong 10.11 average 10.09 average 9.83 average 9.84very strong 7.28 average 7.27 average 6.48 weak 6.46 weak 6.00 weak 6.00weak 5.81 average 5.805 average 5.68 average 5.676 strong 5.40 very weak5.391 very weak 5.22 weak 5.217 weak 5.12 weak 5.124 weak 5.03 strong5.032 very strong 4.88 strong 4.878 very strong 4.33 very weak 4.341weak 4.22 weak 4.215 weak 4.18 average 4.181 average 4.08 average 4.079average 3.95 weak 3.946 weak 3.46 average 3.463 average 3.42 weak 3.428weak

The invention relates in particular to the crystalline hexahydrate ofthe magnesium salt of(S)—N-(1-carboxy-2-methylprop-1-yl)-N-pentanoyl-N-[2′-(1H-tetrazol-5-yl)biphenyl-4-ylmethyl]-amine,a crystalline solid which is clearly characterised by the data andparameters obtained from single crystal X-ray analysis. An in-depthdiscussion of the theory of the methods of single crystal X-raydiffraction and the definition of the evaluated crystal data and theparameters may be found in Stout & Jensen, X-Ray StructureDetermination; A Practical Guide, Mac Millian Co., New York, N.Y. (1968)chapter 3.

The data and parameters of the single crystal X-ray analysis for themagnesium-valsartan-hexahydrate are given in Table 9. TABLE 9 Crystaldata and parameters of the hexahydrate of the magnesium salt ofvalsartan Crystal data sum formula (C₂₄H₂₇N₅O₃)²⁻Mg²⁺•6H₂O molecularmass 565.91 crystal colour colourless crystal shape flat prisms crystalsystem monoclinic space group C2 size of the single crystal 0.013 · 0.50· 0.108 mm³ dimensions and angle of elementary cell a = 40.075(8) Å b =7.400(1) Å c = 10.275(2) Å α = 90° β = 100.85(3)° γ = 90° volume ofelementary cell V_(c) = 2992.6(9) Å³ number of molecules in the 4elementary cell F (000) 1208 measurement range of cell parameters (⊙)2.82-11.15° calculated density 1.256 (g · cm⁻³) linear absorptioncoefficient 0.114 mm⁻¹ X-ray measurement data diffractometer EnrafNonius CAD4 X-radiation (graphite monochromator) MoKα wavelength 0.71073temperature 295 K scan range (θ) 1.03-26.00° scan mode ω/2 Θ reflectionscollected/unique 5954/5868 number of significant reflections 1341 (I >2σ(I)) variation in intensity <1% absorption correction numericStructure refinement method full matrix, least squares, F² number ofparameters 243 agreement index (R) 10.7% weighted agreement index(R_(w)) 13.8% S factor (Goodness of fit) 1.001 number of reflectionsused 5868 determination of hydrogen atoms majority according to the“riding” model, nine H-atoms from water molecules isotropically refinedfrom difference- Fourier calculation extinction correction 0.00098 (10)maximum/minimum residual electron 0.473/−0.614 (e.Å⁻³) density in finaldifference- Fourier calculation absolute structure parameters 0.0(10)Computer programmes used SHELXS 86 (Sheldrick, Göttingen, 1990) SHELXL96 (Sheldrick, Göttingen, 1996) SCHAKAL 86 (Keller, Freiburg 1986)PLATON (Spek, Acta Cryst., 1990)

The elementary cell is defined by six parameters, namely by the gratingconstants a, b and c, and by the axial angle, namely by a, β, und γ. Inthis way, the volume of the elementary cell V_(c) is determined. Adifferentiated description of these crystal parameters is illustrated inchapter 3 of Stout & Jensen (see above).

The details for the hexahydrate of the magnesium salt of valsartan fromthe single crystal measurements, especially the atom coordinates, theisotropic thermal parameters, the coordinates of the hydrogen atoms aswell as the corresponding isotropic thermal parameters, show that amonoclinic elementary cell exists, its cell content occurring from fourformula units Mg²⁺ Valsartan.6 H₂O.

Given the acentric space group C2 determined from the single crystalX-ray structure determination, a racemate is ruled out. Thus theenantiomeric purity of the S-configuration for the crystallinehexahydrate of the magnesium salt of valsartan is proved.

Table 10 illustrates the mass change, i.e. the water absorption or lossas a function of relative humidity at 25° C. for a sample of 9.5 mg ofmagnesium-valsartan-hexahydrate and for a period of 4 hours (h). Thefollowing cycles of changes in relative humidity are shown: 40-90; 90-0;0-90; 90-0 % relative humidity: TABLE 10 relative water relative waterhumidity absorption or humidity absorption in % loss in % in % or lossin % 40 0.06 10 −0.12 50 0.14 0 −4.3 60 0.19 10 −0.79 70 0.25 20 −0.1480 0.41 30 −0.05 90 0.58 40 0.02 80 0.32 50 0.09 70 0.22 60 0.14 60 0.1470 0.20 50 0.08 80 0.28 40 0.16 90 0.51 30 −0.03 0 −3.68 20 −0.07(starting value) −0.01

The measurement error of this sorption method based on thermogravimetryis about 0.1%. Therefore, the hexahydrate of the magnesium salt ofvalsartan under the conditions employed, which are realistic from apharmaceutical-galenic point of view, shows weak, reproducible waterabsorption or water loss in a range of 20 to 80% relative humidity. Thisis surprising to a large extent, since the hexahydrate, which hasincorporated about 19% bound water in the crystal structure, reversiblyabsorbs or releases water even at extreme values of relative humidityand is relatively insensitive at an average range of relative humidity.This characteristic enables an uncomplicated physical-chemical processto be developed and allows a choice of the best dosage forms for thepatients.

The exceptional stability of the magnesium salt of valsartan, especiallythe hexahydrate thereof, towards water may also be shown in stabilitytests In these, the water content of the hexahydrate of the magnesiumsalt of valsartan remains constant both in an open container and in asealed ampoule after four weeks at 40° C. and 75% relative humidity.

Owing to the advantageous crystallinity of the magnesium salt,especially the hexahydrate thereof, this salt is suitable for pressingdirectly to form corresponding tablet formulations.

In addition, an improved dissolving profile in a tablet can be assured.In studies of the dissolving profile, it was established that themagnesium salt, especially the hexahydrate thereof, is released by 100%from a film-coated tablet within 15 minutes.

In addition, the magnesium salt of valsartan, especially the hexahydratethereof, shows an advantageous compression hardness profile.

Calcium/magnesium mixed salts of valsartan also have advantageousproperties, for example uniform crystal conglomerates may be produced.These may be advantageously used in the galenic formulation.

The intrinsic dissolving rates of the di-potassium salt of valsartan atpH 1, pH 4.5 and pH 6.8 show improved values over those of valsartan.

A further object of the invention is the preparation of the saltsaccording to the invention.

The salts according to the invention, including amorphous or crystallineforms thereof, may be prepared as follows:

To form the salt, the process is carried out in a solvent system, inwhich the two reactants, namely the acid valsartan and the respectivebase, are sufficiently soluble. It is expedient to use a solvent orsolvent mixture, in which the resulting salt is only slightly soluble ornot soluble at all, in order to achieve crystallisation orprecipitation. One variant for the salt according to the invention wouldbe to use a solvent in which this salt is very soluble, and tosubsequently add an anti-solvent to this solution, that is a solvent inwhich the resulting salt has only poor solubility. A further variant forsalt crystallisation consists in concentrating the salt solution, forexample by heating, if necessary under reduced pressure, or by slowlyevaporating the solvent, e.g. at room temperature, or by seeding withthe addition of seeding crystals, or by setting up water activityrequired for hydrate formation.

The solvents that may be used are for example C₁-C₅-alkanols, preferablyethanol and isopropanol, as well as C₁-C₅-dialkylketones, preferablyacetone and mixtures thereof with water.

The antisolvents for salt crystallisation may be for exampleC₃-C₇-alkylnitriles, especially acetonitrile, esters, especiallyC₂-C₇-alkanecarboxylic acid-C₁-C₅-alkylester, such as ethyl or isopropylacetate, di-(C₁-C₅-alkyl)-ethers, such as tert.-butylmethylether,furthermore tetrahydrofuran, and C₅-C₈-alkanes, especially pentane,hexane or heptane.

To produce hydrates, a dissolving and crystallising process is used inparticular, or a water-equilibrating crystallisation process.

The dissolving and crystallising process is characterised in that

(i) valsartan and the appropriate base are brought to a reaction in apreferably water-containing, organic solvent,

(ii) the solvent system is concentrated, for example by heating, ifnecessary under reduced pressure and by seeding with seeding crystals orby slowly evaporating, e.g. at room temperature, then crystallisation orprecipitation is initiated and

(iii) the salt obtained is isolated.

In the dissolving and crystallising process, the water-containing,organic solvent system employed is advantageously a mixtures ofalcohols, such as ethanol, and water, or or alkyl-nitrile, especiallyacetonitrile, and water.

The equilibrating crystallisation process for producing hydrates ischaracterised in that

(i) valsartan and the appropriate base are added to a water-containingorganic solvent,

(ii) the solvent is concentrated, for example by heating, if necessaryunder reduced pressure or by slowly evaporating, e.g. at roomtemperature,

(iii) the residue of evaporation is equilibrated with the requiredamount of water by

(a) suspending the residue of evaporation, which is advantageously stillwarm, and which still contains some water, in an appropriate solvent or

(b) by equilibrating the water excess in the solvent; whereby in a) andb) the existing or added water is present in a quantity in which thewater dissolves in the organic solvent and does not form an additionalphase; and

(iv) the salt obtained is isolated.

The solvent system used as the water-containing organic solventadvantageously comprises mixtures of suitable alcohols, such asC₁-C₇-alkanols, especially ethanol, and water.

An appropriate solvent for equilibration is, for example, an ester suchas C₁-C₇-alkane-carboxylic acid-C₁-C₇-alkylester, especially ethylacetate, or a ketone such as di-C₁-C₅-alkylketone, especially acetone.

The equilibration process is notable for example for its high yields andoutstanding reproducibility.

When producing the mono-alkali metal salts according to the presentinvention, predominantly amorphous forms are obtained. On the otherhand, the di-alkali metal salts and alkaline earth metal salts of thepresent invention may also be obtained in crystalline form and are inthe form of hydrates throughout, from appropriate solvents that areconventionally used in production processes, such as esters, e.g.C₁-C₇-alkanecarboxylic acid-C₁-C₇-alkylesters, especially ethyl acetate,ketones, e.g. di-C₁-C₅-alkylketones, especially acetone,C₃-C₇₋alkylnitriles, especially acetonitrile, or ethers, e.g.di-(C₁-C₅-alkyl)-ethers, such as tert.-butylmethylether, alsotetrahydrofuran, or mixtures of solvents. By using the dissolving andcrystallising process, or the water-equilibrating crystallisationprocess, the defined hydrates, which are present in crystalline and inpolymorphous forms, may be obtained reproducibly.

The preparation of the hydrate-free bis-dialkylammonium salts of thepresent invention is advantageously effected in one step by using anappropriate solvent which is optionally mixed with an antisolvent. Inthis way, crystalline salts are obtained.

As a rule, the amino acid salts of the present invention are obtained inamorphous form.

The processes for forming salts are likewise objects of the presentinvention.

These salts or salt hydrates according to the invention are obtained forexample by neutralising the acid valsartan with a base corresponding tothe respective cation. This neutralisation is suitably effected in anaqueous medium, e.g. in water or a mixture of water and a solvent inwhich valsartan is more soluble than in water. Salts with weaker basesmay be converted into other salts either by treating with stronger basesor by treating with acids and then neutralising with other bases.

Crystallisation, especially of the alkaline earth salt hydrates, iseffected in water or an aqueous medium, which consists of water and atleast one solvent that is miscible or partially miscible with water,i.e. not too non-polar, e.g. an alkanol such as methanol, ethanol,propanol, isopropanol, butanol, acetone, methyl ethyl ketone,acetonitrile, DMF, DMSO. The alkanol portion amounts to about 10 to 90,or 20 to 70, advantageously 30 to 50% by volume. For higher alkanols,the less polar solvent may also be present in lower concentrations.Owing to the restricted water-solubility of valsartan, the processfrequently takes place in suspensions, or if valsartan is soluble in theother solvent component, in a solution.

In one embodiment, for example to produce the calcium salt of valsartan,an aqueous solution of valsartan is neutralised with a calcium hydroxidesolution at room temperature and the solution is left to crystallise. Ina preferred procedure, crystallisation is effected from a solventmixture of water/ethanol, the ethanol proportion amounting to ca. 30 to50% by volume. In an especially preferred form, crystallisation iseffected in a closed system by transporting through a low temperaturegradient (especially 1-2° C. at 40° C.) in 30% by volume of ethanol.

In a preferred variant, crystallisation may be optimised, e.g.accelerated, by adding at least one seed crystal.

The salts according to the invention may be used e.g. in the form ofpharmaceutical preparations, which contain the active substance e.g. ina therapeutically effective amount of the active substance, optionallytogether with a pharmaceutically acceptable carrier, for example with aninorganic or organic, solid or optionally also liquid pharmaceuticallyacceptable carrier, which is suitable for enteral, e.g. oral, orparenteral administration.

The invention relates in particular to a pharmaceutical composition,especially in a solid dosage unit, preferably for oral administration,optionally together with a pharmaceutically acceptable carrier.

Pharmaceutical preparations of this kind may be used for example for theprophylaxis and treatment of diseases or conditions which may beinhibited by blocking the AT₁ receptor for example

a disease or condition selected from the group consisting of

(a) hypertension, congestive heart failure, renal failure, especiallychronic renal failure, restenosis after percutaneous transluminalangioplasty, and restenosis after coronary artery bypass surgery;

(b) atherosclerosis, insulin resistance and syndrome X, diabetesmellitus type 2, obesity, nephropathy, renal failure, e.g. chronic renalfailure, hypothyroidism, survival post myocardial infarction (MI),coronary heart diseases, hypertension in the elderly, familialdyslipidemic hypertension, increase of formation of collagen, fibrosis,and remodeling following hypertension (antiproliferative effect of thecombination), all these diseases or conditions associated with orwithout hypertension;

(c) endothelial dysfunction with or without hypertension,

(d) hyperlipidemia, hyperlipoproteinemia, atherosclerosis andhypercholesterolemia, and

(e) glaucoma.

Primary usages are for the treatment of high blood pressure andcongestive heart failure, as well as post-myocardial infarction.

The person skilled in the pertinent art is fully enabled to select arelevant and standard animal test model to prove the hereinbefore andhereinafter indicated therapeutic indications and beneficial effects.

The pharmaceutical activities as effected by administration ofrepresentatives of the salts of the present invention or of thecombination of active agents used according to the present invention canbe demonstrated e.g. by using corresponding pharmacological models knownin the pertinent art. The person skilled in the pertinent art is fullyenabled to select a relevant animal test model to prove the hereinbeforeand hereinafter indicated therapeutic indications and beneficialeffects.

These beneficial effects can, for example, be demonstrated in the testmodel as disclosed by G. Jeremic et al. in J. Cardovasc. Pharmacol.27:347-354, 1996.

For example, the valuable potential of the salts or combinations of thepresent invention for the prevention and treatment of myocardialinfarction can be found using the following test model.

Study Design

In the study to be performed, permanent coronary artery occlusion (CAO)in rats is used as a model of acute myocardial infarction. Theexperiments are carried out with 5 treatment groups characterized byfollowing features:

sham-operated animals

CAO + vehicle

CAO + a salt according to the present invention, optionally

CAO + a salt according to the present invention + a combination partner.

During the study following variables are measured:

infarct size

LV chamber volume

interstitial and perivascular collagen density in spared LV myocardium

COL-I and COL-III protein content in spared LV myocardium by Westernblot

cardiomyocytes cross-sectional area and length in sections of LVmyocardium

plasma concentrations of renin and aldosterone

urine concentration of sodium, potassium and aldosterone

blood pressure in conscious animals

LV and carotid blood pressure in anesthetized animals.

Methodology

Infarct size: Six μm-thick transverse histological sections of the leftventricle are stained with nitroblue tetrazolium and acquired by a B/WXC-77CE CCD video camera (Sony). The resulting image is processed on aKS 300 image analysis system (Carl Zeiss Vision) using a softwarespecifically developed (Porzio et al., 1995). A single operator blindedto treatment interactively defines the boundaries of theinterventricular septum, and the infarcted area on each section issemiautomatically identified as the area of unstained ventriculartissue. The software automatically calculates for each component of theventricular section defined as the chamber, septum, infarcted area,infarcted LV wall and viable LV wall, a set of geometric parameters(Porzio et al., 1995).

Histology: Hearts are fixed in situ, by retrograde perfusion withbuffered 4% formaldehyde after arrest in diastole by i.v. injection of0.5 M KCl. After fixation, the left ventricle (LV) and the free wall ofthe right ventricle are separately weighed; LV longer diameter ismeasured with a caliper. LV histological sections are stained withhematoxylin & eosin for qualitative examination and to quantifycardiomyocytes cross-sectional area with a semi-automated image analysisroutine. Interstitial collagen deposition in LV is evaluated on Siriusred stained sections with a semi-automated image analysis routine(Masson et al., 1998).

Collagen content in LV spared myocardium: LV tissue in the sparedmyocardium is homogenized, subjected to PAGE-SDS electrophoresis andelectroblotted onto nitrocellulose membrane. The blots are exposed toprimary antibodies, i.e. rabbit anti-rat collagen type I or type IIIantiserum (Chemicon). The primary antibodies are recognized by secondaryantibodies conjugated to alkaline phosphatase (for colagen type I) orperoxidase (collagen type III).

Left ventricular chamber volume: LV chamber volume is determined inhearts arrested in diastole (KCl) and fixed in formalin under ahydrostatic pressure equivalent to the measured LV end-diastolicpressure. A metric rod is inserted into the LV to measure LV innerlength. The transverse diameters of the LV chamber are measured in two1-mm thick transverse sections near to the base and the apex of theventricle (Jeremic et al, 1996). The chamber volume is computed from anequation integrating transverse diameters and inner length.

Systemic and Left ventricular hemodynamics: A microtip pressuretransducer (Millar SPC-320) connected to a recorder (Windograf, GouldElectronics) is inserted into the right carotid artery to recordsystolic and diastolic blood pressures. The pressure transducer isadvanced into the LV to measure LV systolic (LVSP) and end-diastolic(LVEDP) pressures, the first derivative of LV pressure overtime (+dP/dt)and heart rate.

Non-invasive blood pressure: Systolic blood pressure and heart rate aremeasured by the tail-cuff method (Letica LE 5002) in conscious rats.

Urine electrolytes, hormones: Rats are individually housed in metaboliccages and 24-h urine collected on 1 ml HCl 6N. Water intake is measured.Urine catecholamines are extracted on Bondelut C₁₈ columns (Varian),separated by HPLC (Apex-II C18, 3 μm, 50×4.5 mm analytical column, JonesChromatography) and quantified with an electrochemical detector(Coulochem II, ESA) (Goldstein et al., 1981). Plasma and urinealdosterone, and plasma angiotensin II is determined with specificradioimmunoassays (Aldoctk-2, DiaSorin and Angiotensin II, NicholsDiagnostics). Urine sodium and potassium are measured by flammephotometry.

Sample Size

10 animals analyzable in each treatment groups are sufficient to detectbiologically significant differences. Only rats with an infarct size ofat least 10% of the LV section area are included in the final analysis.

Endothelial dysfunction is being acknowledged as a critical factor invascular diseases. The endothelium plays a bimodal role as the source ofvarious hormones or by-products with opposing effects: vasodilation andvasoconstriction, inhibition or promotion of growth, fibrinolysis orthrombogenesis, production of anti-oxidants or oxidising agents.Genetically predisposed hypertensive animals with endothelialdysfunction constitute a valid model for assessing the efficacy of acardiovascular therapy.

Endothelial disfunction is characterized by, for example, increasedoxidative stress, causing decreased nitric oxide, increased factorsinvolved in coagulation or fibrinolysis such as plasminogen activatinginhibitor-1 (PAI-1), tissue factor (TF), tissue plasminogen activator(tPA), increased adhesion molecules such as ICAM and VCAM, increasedgrowth factors such as bFGF, TGFb, PDGF, VEGF, all factors causing cellgrowth inflammation and fibrosis.

The treatment e.g. of endothelian dysfunction can be demonstrated in thefollowing pharmacological test:

Material and Methods

Male 20-24 week-old SHR, purchased from RCC Ldt (Füllingsdorf,Switzerland), are maintained in a temperature- and light-controlled roomwith free access to rat chow (Nafag 9331, Gossau, Switzerland) and tapwater. The experiment is performed in accordance with the NIH guidelinesand approved by the Canton Veterinary office (Bew 161, KantonalesVeterinäramt, Liestal, Switzerland). All rats are treated with the NOsynthesis inhibitor L-NAME (Sigma Chemicals) administered in drinkingwater (50 mg/l) for 12 weeks. The average daily dose of L-NAMEcalculated from the water consumed was 2.5 mg/kg/d (range 2.1-2.7).

The rats can be divided into 2 or 3 groups: group 1, control (n=e.g.40); Group 2, a salt according to the present invention; n=e.g. 40); fortesting combinations Group 3, combination partner;(n=e.g. 30). The drugsare administered in drinking fluid. The pressure effect of Ang II at 1mg/kg obtained in controls normotensive rats can be reduced aftertreatment with a salt according to the present invention (Gervais et al.1999).

Body weight is measured every week. Systolic blood pressure and heartrate are recorded by tail cuff plethysmography 3 and 2 weeks beforestarting the study and at 2 weeks after drug administration. Urine iscollected over a 24 hour period from rats kept in individual (metabolic)cages the week before starting treatment and at weeks 4 and 12 forvolume measurement and protein, creatinine, sodium and potassiumdetermination using standard laboratory methods. At the same timepoints, blood samples are withdrawn from the retro-orbital plexus(maximum 1 ml) for creatinine, Na⁺ and K⁺ assays.

Ten rats from each group are sacrificed at 4 weeks for collection ofkidney and heart for morphological analysis. The remaining rats aresacrificed at 12 weeks. Cardiac and kidney weight is recorded. Terminalblood sampling is performed in 5% EDTA at 4 (morphometry study) and 12(end of the study) weeks for aldosterone, determination byradioimmunoassay using a DPC coat-a-count aldosterone-RIA kit (Bühlmann,Switzerland).

Statistical Analysis:

All data are expressed as mean ± SEM. Statistical analysis is performedusing a one-way ANOVA, followed by a Duncan's multiple range test and aNewman-Keuls test, 7 for comparison between the different groups.Results with a probability value of less than 0.05 are deemedstatistically significant.

An improvement of regression of artherosclerosis without effecting theserum lipid levels can, for example, be demonstrated by using the animalmodel as disclosed by H. Kano et al. in Biochemical and BiophysicalResearch Communications 259, 414-419 (1999).

That the salts or combinations according to the present invention can beused for the regression of a cholesterol diet-induced atherosclerosis,can be demonstrated using the test model described, e.g., by C. Jiang etal. in Br. J. Pharmacol. (1991), 104, 1033-1037.

That the salts or combinations according to the present invention can beused for the treatment of renal failure, especially chronic renalfailure, can be demonstrated using the test model described, e.g., by D.Cohen et al. in Journal of Cardiovascular Pharmacology, 32: 87-95(1998).

The present pharmaceutical preparations which, if so desired, maycontain further pharmacologically active substances, are prepared in amanner known per se, for example by means of conventional mixing,granulating, coating, dissolving or lyophilising processes, and containfrom about 0.1% to 100%, especially from about 1% to about 50%, oflyophilisates up to 100% of the active substance.

The invention similarly relates to compositions containing the saltsaccording to the invention.

The invention similarly relates to the use of the salts according to theinvention preferably for the production of pharmaceutical preparations,especially for the prophylaxis and also for the treatment of diseases orconditions which may be inhibited by blocking the AT₁ receptor. Primaryusages are for the treatment of high blood pressure and congestive heartfailure, as well as post-myocardial infarction.

The invention similarly relates to the use for the prophylaxis andtreatment of diseases or conditions which may be inhibited by blockingthe AT₁ receptor, characterised in that a patient, including a humanpatient, requiring such treatment is administered with a therapeuticallyeffective amount of a salt according to the invention, optionally incombination with at least one composition for the treatment ofcardiovascular diseases and related conditions and diseases listedhereinbefore or hereinafter.

The invention similarly relates to combinations, e.g. pharmaceuticalcombinations, containing a salt of the present invention or in each casea pharmaceutically acceptable salt thereof in combination with at leastone composition for the treatment of cardiovascular diseases and relatedconditions and diseases as listed hereinbefore or hereinafter, or ineach case a pharmaceutically acceptable salt thereof. Combinations withother compositions for the treatment of cardiovascular diseases andrelated conditions and diseases as listed hereinbefore or hereinafter,or in each case a pharmaceutically acceptable salt thereof, are likewiseobjects of the present invention.

The combination may be made for example with the following compositions,selected from the group consisting of a:

(i) HMG-Co-A reductase inhibitor or a pharmaceutically acceptable saltthereof,

(ii) angiotensin converting enzyme (ACE) Inhibitor or a pharmaceuticallyacceptable salt thereof,

(iii) calcium channel blocker or a pharmaceutically acceptable saltthereof,

(iv) aldosterone synthase inhibitor or a pharmaceutically acceptablesalt thereof,

(v) aldosterone antagonist or a pharmaceutically acceptable saltthereof,

(vi) dual angiotensin converting enzyme/neutral endopeptidase (ACE/NEP)inhibitor or a pharmaceutically acceptable salt thereof,

(vii) endothelin antagonist or a pharmaceutically acceptable saltthereof,

(viii) renin inhibitor or a pharmaceutically acceptable salt thereof,and

(ix) diuretic or a pharmaceutically acceptable salt thereof.

HMG-Co-A reductase inhibitors (also calledβ-hydroxy-β-methylglutaryl-co-enzyme-A reductase inhibitors) areunderstood to be those active agents that may be used to lower the lipidlevels including cholesterol in blood.

The class of HMG-Co-A reductase inhibitors comprises compounds havingdiffering structural features. For example, mention may be made of thecompounds that are selected from the group consisting of atorvastatin,cerivastatin, compactin, dalvastatin, dihydrocompactin, fluindostatin,fluvastatin, lovastatin, pitavastatin, mevastatin, pravastatin,rivastatin, simvastatin, and velostatin, or, in each case, apharmaceutically acceptable salt thereof.

Preferred HMG-Co-A reductase inhibitors are those agents which have beenmarketed, most preferred is fluvastatin and pitavastatin or, in eachcase, a pharmaceutically acceptable salt thereof.

The interruption of the enzymatic degradation of angiotensin I toangiotensin II with so-called ACE-inhibitors (also called angiotensinconverting enzyme inhibitors) is a successful variant for the regulationof blood pressure and thus also makes available a therapeutic method forthe treatment of congestive heart failure.

The class of ACE inhibitors comprises compounds having differingstructural features. For example, mention may be made of the compoundswhich are selected from the group consisting alacepril, benazepril,benazeprilat, captopril, ceronapril, cilazapril, delapril, enalapril,enaprilat, fosinopril, imidapril, lisinopril, moveltopril, perindopril,quinapril, ramipril, spirapril, temocapril, and trandolapril, or, ineach case, a pharmaceutically acceptable salt thereof.

Preferred ACE inhibitors are those agents that have been marketed, mostpreferred are benazepril and enalapril.

The class of CCBs essentially comprises dihydropyridines (DHPs) andnon-DHPs such as diltiazem-type and verapamil-type CCBs.

A CCB useful in said combination is preferably a DHP representativeselected from the group consisting of amlodipine, felodipine, ryosidine,isradipine, lacidipine, nicardipine, nifedipine, niguldipine,niludipine, nimodipine, nisoldipine, nitrendipine, and nivaldipine, andis preferably a non-DHP representative selected from the groupconsisting of flunarizine, prenylamine, diltiazem, fendiline,gallopamil, mibefradil, anipamil, tiapamil and verapamil, and in eachcase, a pharmaceutically acceptable salt thereof. All these CCBs aretherapeutically used, e.g. as anti-hypertensive, anti-angina pectoris oranti-arrhythmic drugs. Preferred CCBs comprise amlodipine, diltiazem,isradipine, nicardipine, nifedipine, nimodipine, nisoldipine,nitrendipine, and verapamil, or, e.g. dependent on the specific CCB, apharmaceutically acceptable salt thereof. Especially preferred as DHP isamlodipine or a pharmaceutically acceptable salt, especially thebesylate, thereof. An especially preferred representative of non-DHPs isverapamil or a pharmaceutically acceptable salt, especially thehydrochloride, thereof.

Aldosterone synthase inhibitor is an enzyme that converts corticosteroneto aldosterone to by hydroxylating cortocosterone to form18-OH-corticosterone and 18-OH-corticosterone to aldosterone. The classof aldosterone synthase inhibitors is known to be applied for thetreatment of hypertension and primary aldosteronism comprises bothsteroidal and non-steroidal aldosterone synthase inhibitors, the laterbeing most preferred.

Preference is given to commercially available aldosterone synthaseinhibitors or those aldosterone synthase inhibitors that have beenapproved by the health authorities.

The class of aldosterone synthase inhibitors comprises compounds havingdiffering structural features. For example, mention may be made of thecompounds which are selected from the group consisting of thenon-steroidal aromatase inhibitors anastrozole, fadrozole (including the(+)-enantiomer thereof), as well as the steroidal aromatase inhibitorexemestane, or, in each case where applicable, a pharmaceuticallyacceptable salt thereof.

The most preferred non-steroidal aldosterone synthase inhibitor is the(+)-enantiomer of the hydrochloride of fadrozole (U.S. Pat. Nos.4,617,307 and 4,889,861) of formula

A preferred steroidal aldosterone antagonist is eplerenone of theformula

spironolactone.

A preferred dual angiotensin converting enzyme/neutral endopetidase(ACE/NEP) inhibitor is, for example, omapatrilate (cf. EP 629627),fasidotril or fasidotrilate, or, if appropriable, a pharmaceuticallyacceptable salt thereof.

A preferred endothelin antagonist is, for example, bosentan (cf. EP526708 A), furthermore, tezosentan (cf. WO 96/19459), or in each case, apharmaceutically acceptable salt thereof.

A renin inhibitor is, for example, a non-peptidic renin inhibitor suchas the compound of formula

chemically defined as2(S),4(S),5(S),7(S)—N-(3-amino-2,2-dimethyl-3-oxopropyl)-2,7-di(1-methylethyl)-4-hydroxy-5-amino-8-[4-methoxy-3-(3-methoxy-propoxy)phenyl]-octanamide.This representative is specifically disclosed in EP 678503 A. Especiallypreferred is the hemi-fumarate salt thereof.

A diuretic is, for example, a thiazide derivative selected from thegroup consisting of chlorothiazide, hydrochlorothiazide,methylclothiazide, and chlorothalidon. The most preferred ishydrochlorothiazide.

Preferably, the jointly therapeutically effective amounts of the activeagents according to the combination of the present invention can beadministered simultaneously or sequentially in any order, separately orin a fixed combination.

The structure of the active agents identified by generic or tradenamesmay be taken from the actual edition of the standard compendium “TheMerck Index” or from databases, e.g.

Patents International (e.g. IMS World Publications). The correspondingcontent thereof is hereby incorporated by reference. Any person skilledin the art is fully enabled to identify the active agents and, based onthese references, likewise enabled to manufacture and test thepharmaceutical indications and properties in standard test models, bothin vitro and in vivo.

The corresponding active ingredients or a pharmaceutically acceptablesalts thereof may also be used in form of a solvate, such as a hydrateor including other solvents, used for crystallization.

The compounds to be combined can be present as pharmaceuticallyacceptable salts. If these compounds have, for example, at least onebasic center, they can form acid addition salts. Corresponding acidaddition salts can also be formed having, if desired, an additionallypresent basic center. The compounds having an acid group (for exampleCOOH) can also form salts with bases.

In a variation thereof, the present invention likewise relates to a“kit-of-parts”, for example, in the sense that the components to becombined according to the present invention can be dosed independentlyor by use of different fixed combinations with distinguished amounts ofthe components, i.e. simultaneously or at different time points. Theparts of the kit of parts can then e.g. be administered simultaneouslyor chronologically staggered, that is at different time points and withequal or different time intervals for any part of the kit of parts.Preferably, the time intervals are chosen such that the effect on thetreated disease or condition in the combined use of the parts is largerthan the effect that would be obtained by use of only any one of thecomponents.

The invention furthermore relates to a commercial package comprising thecombination according to the present invention together withinstructions for simultaneous, separate or sequential use.

Dosaging may depend on various factors, such as mode of application,species, age and/or individual condition. For oral application, thedoses to be administered daily are between ca. 0.25 and 10 mg/kg, andfor warm-blooded animals with a body weight of ca. 70 kg, preferablybetween ca. 20 mg and 500 mg, especially 40 mg, 80 mg, 160 mg and 320 mgbased on the free acid.

The invention is illustrated in particular by the examples and alsorelates to the new compounds named in the examples and to their usageand to methods for the preparation thereof.

The following examples serve to illustrate the invention withoutlimiting the invention in any way.

For example, the di-potassium salt of valsartan is formed, especially ahydrate thereof. The di-potassium salt is noted in particular for itsmarked water solubility. The crystalline tetrahydrate of thedi-potassium salt of valsartan, with a melting point of 135.0° C., maybe mentioned in particular. According to elementary analysis, a certainsample of this hydrate has a water content of 3.72 mols of water per molof di-potassium salt. For high relative humidity at room temperature,the tetrahydrate is formed and for low values of relative humidity, theanhydrate of the di-potassium salt is formed.

A magnesium salt of valsartan is similarly produced, in this instance asan amorphous solid with 3.4% H₂O. The temperature of glass transition,as a mean value of the stage of the specific heat of 0.85 J·[g·⁰C]⁻¹ is167° C. No melting point is observed. Both facts, namely the glasstransition and the absence of a melting point, together with themeasured value of the change in specific heat, confirm that thismagnesium salt of valsartan is practically 100% amorphous. According toa stereo-specific chromatography method, the enantiomer purity of thisamorphous magnesium salt has been determined as 83%.

EXAMPLE 1 Production of the calcium salt as the tetrahydrate in situ of(S)—N-(1-carboxy-2-methyl-prop-1-yl)-N-pentanoyl-N-[2′-(1H-tetrazol-5-yl)-biphenyl-4-ylmethyl]-amine

21.775 g of (S)—N-(1-carboxy-2-methyl-prop-1-yl)-N-pentanoyl-N-[2′-(1H-tetrazol-5-yl)-biphenyl-4-ylmethyl]-amine are dissolved at roomtemperature in 300 ml of ethanol. By careful addition of 300 ml ofwater, the ethanol concentration is reduced to 50% by volume. Using amagnetic stirrer, 3.89 g of Ca(OH)₂ are added slowly in small portionsto this clear, slightly acidic (pH 4) solution, so that the pH valuetemporarily does not exceed a value of ca. 8. Because it absorbs CO₂from the air, the Ca(OH)₂ used contains traces of CaCO₃; therefore theadded amount includes an excess of 5%. After adding the stoichiometricamount of Ca(OH)₂, the pH is ca. 6, and after adding the excess it risesto 7. The solution becomes turbid through the small amount of finelydivided CaCO₃ , which is removed through a folded filter. The productcontained in the solution crystallises continuously upon removal of thealcohol content by allowing to stand at room temperature. The procedurecan be accelerated by using a flat dish in a recirculating air drier at40° C. After concentrating to ca. one half, the alcohol content of thesolution drops to ca. 10% by volume and most of the productcrystallises. It is filtered, rinsed for a short time with 10% by volumeethanol and dried at 40° C. until reaching a constant weight.(S)—N-(1-carboxy-2-methyl-prop-1-yl)-N-pentanoyl-N-[2′-(1H-tetrazol-5-yl)-biphenyl-4-ylmethyl]-aminecalcium salt tetrahydrate is obtained.

The melting point for the tetrahydrate of the calcium salt of valsartan,produced according to example 1, for a heating rate of 10 K·min⁻¹ and ina closed specimen container with a small internal volume is determinedas 205° C. and the melting enthalpy as 92 kJ·Mol⁻¹. The density of thecrystals of the calcium-valsartan-tetrahydrate produced according toexample 1, determined by a helium pycnometer, is 1.297 g·cm⁻³. Thisvalue conforms to the theoretically calculated value of 1.298 g·cm⁻³calculated from the single crystal structure. The optical rotation ofthe tetrahydrate of the calcium salt of valsartan according to example 1is measured in methanol as a 1% solution [a]²⁰ _(D)=+1°.

The enantiomer purity of the salt hydrate produced according to example1 is determined by a stereo-specific HPLC method. The stereo-specificseparation is achieved by a chiral column (Chiral AGP). The enantiomerpurity is determined as ee=100%.

Calculation of the interlattice plane intervals from the X-ray powderpattern taken with a Guinier camera is as follows for the most importantlines for this batch of the tetrahydrate of the calcium salt ofvalsartan:

d in [Å]: 16.27, 9.90, 9.39, 8.04, 7.71, 7.05, 6.49, 6.34, 6.2, 5.87,5.75, 5.66, 5.20, 5.05, 4.95, 4.73, 4.55, 4.33, 4.15, 4.12, 3.95, 3.91,3.87, 3.35.

Elementary analysis gives the following measured values of the elementspresent in calcium-valsartan-tetrahydrate and of water. The waterevaluation was carried out at 130° C. after expulsion. The findings ofthe elementary analysis, within the error limits, correspond to the sumformula (C₂₄H₂₇N₅O₃)²⁻Ca²⁺.4 H₂O. % found % calculated C 52.82 52.83 H6.42 6.47 N 12.91 12.83 O 20.20 20.53 water 13.25 13.21 Ca 7.03 7.35

EXAMPLE 2 Production of the magnesium salt as the hexahydrate in situ of(S)—N-(1-carboxy-2-methyl-prop-1-yl)-N-pentanoyl-N-[2′-(1H-tetrazol-5-yl)-biphenyl-4-ylmethyl]-amine

43.55 g of valsartan[(S)—N-(1-carboxy-2-methyl-prop-1-yl)-N-pentanoyl-N-[2′-(1H-tetrazol-5-yl)-biphenyl-4-ylmethyl]-amine]are dissolved at room temperature in 600 ml of 50% by volume ethanol(from absolute ethanol—see Merck and quarz-bidistilled water). Theslightly turbid solution becomes clear after adding a further 50 ml of50% ethanol. Using a magnetic stirrer, 4.03 g or 0.1 M MgO (Merck p.a.)are slowly added in small portions to this slightly acidic solution witha pH value of 4. The pH value hereby rises to ca. 6. The process iseffected with an excess of 10%, i.e. a further 0.40 g of MgO are added.This excess is not fully dissolved, and the pH value rises to ca. 7.5.The small residue is filtered from the solution through a folded filterand washed with 50 ml of 50% ethanol.

The combined clear solution is carefully concentrated at 40° C. whilststirring with a magnetic stirrer in a large crystallisation dish.Towards the end of this procedure, the solution has a tendency to hardeninto a glassy gel. Scratching with a glass rod induces the in situcrystallisation in this phase, which may be recognised by the whitecolour of the crystalline solid thus formed. The product is dried at 50°C. in a recirculating air drier until reaching a constant weight. Theyield of magnesium-valsartan-hexahydrate is 53.7 g or 95% based on thevalsartan employed as the free acid.

The melting point for the salt hydrate produced according to example 2,namely the magnesium-valsartan-hexahydrate, for a heating rate of 10K·min⁻¹ in a sealed sample container with a small internal volume, in anamount of 2.24 mg, was measured at 132° C. and the melting enthalpy at64 kJ·Mol⁻¹.

The density of the crystals of the hexahydrate of the magnesium salt ofvalsartan produced according to example 2, determined by a heliumpycnometer, is 1.273 g·cm⁻³. This value conforms to the theoreticallycalculated value of 1.256 g·cm⁻³ calculated from the single crystalstructure.

The optical rotation of the magnesium-valsartan-hexahydrate producedaccording to example 2 is measured in methanol as a 1% solution [a]²⁰_(D)=−14°.

The enantiomer purity of the salt hydrate produced according to example2 is determined by a stereo-specific HPLC method. The stereo-specificseparation is achieved by a chiral column (Chiral AGP). The enantiomerpurity is determined as ee=99.6%.

Calculation of the interlattice plane intervals from the X-ray powderpattern taken with a Guinier camera is as follows for the most importantlines for this batch of the magnesium valsartan hexahydrate:

d in [Å]: 19.78, 10.13, 9.84, 7.28, 6.00, 5.81, 5.67, 5.21, 5.04, 4.88,4.21, 4.18, 4.08, 3.95, 3.46, 3.42.

Elementary analysis gives the following measured values of the elementspresent in the hexahydrate of the magnesium salt of valsartan and ofwater. The water evaluation is carried out at 130° C. after expulsion.The findings of the elementary analysis, within the error limits,correspond to the sum formula ( C₂₄H₂₇N₅O₃)²⁻Mg²⁺.6H₂O. % found %calculated C 51.03 50.94 H 7.00 6.95 N 12.45 12.38 O 25.02 25.44 water19.08 19.10 Mg 4.35 4.29

EXAMPLE 3 Production of the hydrate of di-potassium salt of(S)—N-(1-carboxy-2-methyl-prop-1-yl)-N-pentanoyl-N-[2′-(1H-tetrazol-5-yl)-biphenyl-4-ylmethyl]-amine(3.5±1.0 mole H₂O)

5 g of(S)—N-(1-carboxy-2-methyl-prop-1-yl)-N-pentanoyl-N-[2′-(1H-tetrazol-5-yl)-biphenyl-4-ylmethyl]-amineare dissolved whilst heating gently in 11.5 ml of 2 normal potassiumhydroxide solution and mixed with 320 ml of acetonitrile. The mixture isheated for 5 minutes to reflux (turbid solution), left without stirringfor 3 days at room temperature (seeding) and then left for 24 hours at0° C. The mother liquor is decanted. The crystallisate is washed twicewith acetonitrile and then dried in the air for 36 hours until reachinga constant weight.(S)—N-(1-carboxy-2-methyl-prop-1-yl)-N-pentanoyl-N-[2′-(1H-tetrazol-5-yl)-biphenyl-4-ylmethyl]-aminedipotassium salt hydrate is obtained (3.7 mols water per mol dipotassiumsalt). The melting point in a closed specimen container is 135° C.

Elementary analysis: C₂₄H₂₇N₅O₃K₂, 3.72 H₂O, molar mass 578.72 % found %calculated C 49.90 49.81 H 5.92 6.00 N 12.14 12.10 O 18.55 18.58 water11.58 11.58 K 13.50 13.51

X-ray diffraction diagram measured with the diffractometer Scintag Inc.,Cupertino, Calif. 95014, US, using CuKα radiation.

Reflection lines and intensities of the most important lines of thehydrate of the di-potassium salt of valsartan, values given in 20 in °:2θ in° Intensity 4.6 strong 8.8 medium 9.2 strong 11.1 weak 12.5 weak14.8 strong 15.3 weak 16.4 medium 17.8 strong 18.2 medium 18.4 medium18.9 medium 20.4 medium 21.1 weak 21.3 medium 22.3 weak 22.5 strong 23.1medium 23.9 strong 25.6 weak 26.6 strong 26.9 medium 28.1 medium

Preferred are hydrates comprising the medium and strong intensity peaks.TABLE 11 Crystal data and parameters of the hydrate of the di-potassiumsalt of valsartan Crystal data sum formula (C₂₄H₂₇N₅O₃)²⁻2K⁺•x H₂O (x =3.5 ± 1.0) molecular mass 574.78 crystal system orthorhombic space groupP2₁2₁2 a (Å) 38.555(2) b (Å) 7.577(1) c (Å) 10.064(1) V (Å³) 2940.0(5) Z4 F(000) 1212 D_(calc.) (g · cm⁻³) 1.286 number of reflections for cellparameters 25 θ range for cell parameters (°) 30-38 μ (mm⁻¹) 3.24Temperature (° C.) 23 crystal shape prisms crystal size (mm) 0.63 × 0.20× 0.14 crystal colour colourless Data collection diffractometer EnrafNonius CAD4 radiation (graphite monochromator) CuKα wave length (Å)1.54178 scan mode ω/2θ scan range (θ) 3-74 absorption correction nonenumber of measured reflections 3450 number of observed reflections (I >2σ(I)) 2867 h range −48→0 k range −9→0 l range −12→0 number of standardreflections 3 every 120 mins variation in intensity ±5% Structurerefinement refinement method refinement on F², complete matrix number ofparameters 341 R 0.069 R_(w) 0.182 S 1.57 number of reflections used2867 treatment of H-atoms “riding”, apart from those of the watermolecules, which were ignored Δ/σ_(max) 0.24 extinction correction0.0010(5) maximum/minimum residual electron density in0.815/−0.676(eÅ⁻³) final difference-Fourier calculation absolutestructure parameters −0.02(4) Programmes used SHELXS86 (Sheldrick,Göttingen), XHELXL93 (Sheldrick, Göttingen), SCHAKAL92 (Keller,Freiburg)

EXAMPLE 4 Production of the di-potassium salt of(S)—N-(1-carboxy-2-methyl-prop-1-yl)-N-pentanoyl-N-[2′-(1H-tetrazol-5-yl)-biphenyl-4-ylmethyl]-amine

25 g of(S)—N-(1-carboxy-2-methyl-prop-1-yl)-N-pentanoyl-N-[2′-(1H-tetrazol-5-yl)-biphenyl-4-ylmethyl]-amineare dissolved in 200 ml of ethanol. 50 ml of water are added, thesolution cooled to 0° C. and then mixed with 57.4 ml of 2 normalpotassium hydroxide solution. The mixture is concentrated by evaporationon a rotary evaporator, evaporated again with each of toluene andacetonitrile, and dried in a high vacuum for 15 minutes at 50° C. Theproduct is dissolved in 290 ml of a hot mixture of acetonitrile/water(95:5), mixed with an additional 110 ml of acetonitrile, allowed to cooland seeded at ca. 30° C. The mixture is left to stand for 4 days at roomtemperature and filtered by suction. The residue is washed withacetonitrile/water (95:5) and dried in a high vacuum at 80° C.(S)—N-(1-carboxy-2-methyl-prop-1-yl)-N-pentanoyl-N-[2′-(1H-tetrazol-5-yl)-biphenyl-4-ylmethyl]-aminedipotassium salt is obtained as a white powder. Melting point >300° C.

Elementary analysis: The material obtained is hygroscopic and can beequilibrated in the air (C₂₄H₂₇N₅O₃K₂, 3.96 mols H₂O). % found %calculated C 49.15 49.44 H 6.02 6.04 N 11.91 12.01 O 19.18 19.1 water12.23 12.24 K 13.4 13.41

EXAMPLE 5 Production of the di-sodium salt of(S)—N-(1-carboxy-2-methyl-prop-1-yl)-N-pentanoyl-N-[2′-(1H-tetrazol-5-yl)-biphenyl-4-ylmethyl]-amine

1 g of(S)—N-(1-carboxy-2-methyl-prop-1-yl)-N-pentanoyl-N-[2′-(1H-tetrazol-5-yl)-biphenyl-4-ylmethyl]-amineis dissolved in 50 ml of ethanol, mixed with 2.3 ml of 2 normal sodiumhydroxide solution and concentrated by evaporation, and the residue isevaporated with each of ethanol and ethyl acetate. The white residue isstirred in hot acetonitrile and filtered by suction at room temperature.Drying in a high vacuum at 80° C. over night yields(S)—N-(1-carboxy-2-methyl-prop-1-yl)-N-pentanoyl-N-[2′-(1H-tetrazol-5-yl)-biphenyl-4-ylmethyl]-amine disodium salt as a whitepowder. Melting point from 260° C., brownish discolouration at 295° C.

Elementary analysis: The material obtained (hygroscopic) can beequilibrated in the air (C₂₄H₂₇N₅O₃Na₂, 5.36 mols H₂O, molar mass576.05) % found % calculated C 49.79 50.04 H 6.51 6.60 N 12.00 12.16 O23.44 23.22 water 16.75 16.76 Na 8.09 7.98

EXAMPLE 6 Production of the magnesium salt of(S)—N-(1-carboxy-2-methyl-prop-1-yl)-N-pentanoyl-N-[2′-(1H-tetrazol-5-yl)-biphenyl-4-ylmethyl]-amine

5 g of(S)—N-(1-carboxy-2-methyl-prop-1-yl)-N-pentanoyl-N-[2′-(1H-tetrazol-5-yl)-biphenyl-4-ylmethyl]-amineare added to a suspension of 0.666 g of magnesium hydroxide in 20 ml ofwater. 40 ml of methanol are added, then the mixture is stirred for 2hours at room temperature and concentrated. The residue is dissolved inmethanol, filtered through a hard filter, concentrated and evaporatedwith acetonitrile. The product is stirred with hot acetonitrile,filtered by suction at room temperature and dried in a high vacuum at90° C. over night.(S)—N-(1-carboxy-2-methyl-prop-1-yl)-N-pentanoyl-N-[2′-(1H-tetrazol-5-yl)-biphenyl-4-ylmethyl]-aminemagnesium salt is obtained as a white powder. Melting point: The samplebecomes brownish upon heating and vitrifies towards 300° C.

Elementary analysis: C₂₄H₂₇N₅O₃Mg, 0.89 mols H₂O, molar mass: 473.85 %found % calculated C 61.26 60.83 H 6.13 6.12 N 14.88 14.78 O 13.13 water3.39 3.38 Mg 4.74 5.13

EXAMPLE 7 Production of the calcium salt of(S)—N-(1-carboxy-2-methyl-prop-1-yl)-N-pentanoyl-N-[2′-(1H-tetrazol-5-yl)-biphenyl-4-ylmethyl]-amine

5 g of(S)—N-(1-carboxy-2-methyl-prop-1-yl)-N-pentanoyl-N-[2′-(1H-tetrazol-5-yl)-biphenyl-4-ylmethyl]-amineare added to a suspension of 0.851 g of calcium hydroxide in 20 ml ofwater and then mixed with 200 ml of ethanol. The mixture is stirred forone hour at room temperature, concentrated by evaporation to dryness(re-evaporation with acetonitrile), stirred in hot acetonitrile (with atrace each of ethanol and water) and filtered by suction at roomtemperature.

0.95 g of the salt are heated to reflux in 20 ml of acetonitrile/water(1:1), whereby the mixture almost dissolves. The mixture is allowed tocool to room temperature, mixed with 20 ml of acetonitrile, filtered bysuction and washed twice with acetonitrile/water (1:1) and dried overnight in a high vacuum at 80° C. Melting point: from 300° C.(decomposition).

Elementary analysis: C₂₄H₂₇N₅O₃Ca, 1.71 mols H₂O, molar mass 504.39(water evaluation carried out after expulsion at 150° C.). % found %calculated C 56.88 57.15 H 6.13 6.08 N 13.89 13.88 O 14.94 water 6.126.11 Ca 7.94 7.95

EXAMPLE 8 Production of the mono-potassium salt of(S)—N-(1-carboxy-2-methyl-prop-1-yl)-N-pentanoyl-N-[2′-(1H-tetrazol-5-yl)-biphenyl-4-ylmethyl]-amine

2 g of(S)—N-(1-carboxy-2-methyl-prop-1-yl)-N-pentanoyl-N-[2′-(1H-tetrazol-5-yl)-biphenyl-4-ylmethyl]-amineare suspended in 20 ml of water and mixed with 2.296 ml of a 2 normalpotassium hydroxide solution. The mixture is stirred for 30 minutes andmixed with 50 ml of ethanol, whereupon a colourless solution isobtained. The mixture is concentrated by evaporation, evaporated oncemore with acetonitrile and lyophilised from tert.-butanol (with a traceof water).

Elementary analysis (after equilibration in the air). C₂₄H₂₇N₅O₃Ca, 1.69mols H₂O, molar mass 504.06 (water evaluation carried out afterexpulsion at 150° C.). % found % calculated C 57.30 57.19 H 6.35 6.27 N13.61 13.89 O 14.58 14.89 water 6.04 6.04 K 7.72 7.76

EXAMPLE 9 Production of the Magnesium Salt as the Hexahydrate ofValsartan by a Water-Equilibrating Process.

1600 g of valsartan and 6820 g of isopropanol are stirred to form asuspension in a mixing container at room temperature, and added to an 80litre glass receptacle with a stirrer. The mixing container is rinsedwith 3919 g of isopropanol in portions and the rinsing solution added tothe main mixture. After adding 3800 g of deionised water, the mixture istransformed into a homogeneous solution by stirring. Then, 156.3 g ofmagnesium oxide, suspended in 1520 g of deionised water, are added andthe suspension supplemented with 1000 g of deionised water. By slowlystirring at room temperature, the magnesium oxide goes into solution.The pH value of the resulting solution is ca. 7.2. By adding a further2.5 g of magnesium oxide in small portions, the pH value is raised toca. 8.3. The resulting mixture is turbid owing to undissolved particlesof unknown type in the magnesium oxide.

This mixture is transferred through a candle filter to a 35 litre enamelboiler and the glass receptacle and the transfer tube are rinsed with885 g of isopropanol and 1122 g of deionised water. For mildconcentration, a vacuum is created in the boiler to an initialtheoretical value of 89-100 mbar. With a temperature of the heatingmedium of 45-50° C. and a boiling temperature of the mixture of 37-40°C., a total of 13.66 kg of aqueous isopropanol is distilled. By loweringthe distillation pressure to a final value of 10 mbar and simultaneouslyraising the heating medium temperature to 65° C., the amount ofdistillate is increased to a total of 17.12 kg. 9300 g of ethyl acetate,followed by 14.9 g of valsartan Mg salt hexahydrate as seeding crystals,are added to the boiler content whilst stirring. Finally, a further 6680g of ethyl acetate are dispensed in and cooling is effected to roomtemperature whilst stirring. The stirring procedure is maintained for atleast 24 hours. The suspension is then filtered through Büchner filters.A moist filter cake is thus obtained. The boiler is rinsed with 1171 gof ethyl acetate and the rinsing mixture is used to wash the filtercake. Drying of a partial amount on metal sheets in a vacuum dryingchamber at 50 mbar pressure and 40° C. oven temperature for 6.5 hoursuntil reaching a constant weight yields a dry substance.

The physical data, especially the X-ray powder pattern, correspond tothe magnesium hexahydrate salt of example 2.

EXAMPLE 10 Production of the Calcium Salt of Valsartan as theTetrahydrate.

1600 g of valsartan and 7000 g of ethanol are stirred to form asuspension in a mixing container at room temperature, and added to a 35litre enamel boiler with a stirrer. The mixing container is rinsed with2000 g of ethanol in portions and the rinsing solution added to the mainmixture. After adding 9000 g of deionised water, the mixture istransformed into a homogeneous solution by stirring. Then, 272 g ofcalcium hydroxide, suspended in 1500 g of deionised water, are added andthe suspension supplemented with 1300 g of deionised water. By slowlystirring at room temperature, the calcium hydroxide goes into solution.The pH value of the resulting solution is ca. 6.9. By adding a further9.6 g of calcium hydroxide, the pH value is raised to ca. 10.6. Theresulting mixture is turbid owing to undissolved particles (calciumcarbonate) in the calcium hydroxide. This mixture is transferred througha candle filter to a 35 litre enamel boiler and the glass receptacle andthe transfer tube are rinsed with a solution of 1048 g of ethanol and1000 g of deionised water. For mild concentration, a vacuum is createdin the boiler to a theoretical value of 100-120 mbar. With a temperatureof the heating medium of ca. 50° C. and a boiling temperature of themixture of max. 44° C., a total of 11.32 kg of aqueous ethanol isdistilled. The dissolved salt crystallises spontaneously during thecourse of distillation. The suspension present at the end ofdistillation is cooled to ca. 5° C. whilst stirring, and is stirred forca. 16 hours at 5° C. The suspension is then filtered through Büchnerfilters. The boiler is rinsed with a mixture of 3600 ml of deionisedwater and 400 ml of ethanol, the mixture being cooled to 5° C., and therinsing mixture is used to wash the filter cake. A moist filter cake isthus obtained. Drying of a partial amount on metal sheets in a vacuumdrying chamber at 50 mbar pressure and 40° C. oven temperature for 24hours until reaching a constant weight yields a dry substance.

The physical data, especially the X-ray powder pattern, correspond tothe calcium tetrahydrate salt of example 1.

EXAMPLE 11 Hydrate of Valsartan Disodium Salt (2.4±1.0 mole H₂O)

50 ml of 2N sodium hydroxide solution are added dropwise at ca. 25° C.to a solution of 21.5 g of valsartan in 200 ml of isopropanol. The clearsolution (pH ca. 7.2) is concentrated under vacuum at ca. 40° C. Theamorphous residue of the disodium salt is suspended in 100 ml ofisopropanol, and water is removed by concentrating under vacuum oncemore at ca. 40° C. and degassing. The amorphous residue is suspended in75 ml of acetone and 2 ml of water at ca. 40° C. At ca. 25-30° C., 200ml of tert.-butylmethylether are added, whereby constituents that areinitially smeary are gradually transformed into a crystallinesuspension. After stirring over night at ca. 25° C., the suspension iscooled to 10° C. and after ca. 1 hour is filtered by suction whilstexcluding atmospheric moisture. Washing then takes place with 20 ml oftert.-butylmethylether. The moist filter cake is dried over night at ca.30 mbar and at 30° C. A colourless, slightly hygroscopic crystal powderis obtained.

Elementary analysis: C₂₄H₂₇N₅O₃Na₂, 2.44 mols H₂O % found % calculated C55.03 55.07 H 6.16 6.14 N 13.38 13.38 O 16.63 water 8.40 8.41 Na 8.678.78

X-ray diffraction diagram (reflection lines and intensities of the mostimportant lines) of the crystalline hydrate of the disodium salt ofvalsartan measured with the diffractometer Scintag Inc. Cupertino,Calif. 95014, US, using CuKα radiation. 2θ Intensity 4.7 strong 9.1strong 13.3 weak 13.7 weak 15.6 medium 16.4 medium 17.2 medium 17.9medium 18.7 medium 19.6 medium 21.3 medium 21.9 medium 22.8 strong 24.0weak 24.8 weak 25.5 weak 26.5 medium 26.8 weak 27.3 weak 27.8 weak 28.6weak 29.4 weak 29.9 medium

EXAMPLE 12 Hydrate of the Valsartan Dipotassium Salt (3.4±1.0 mole H₂O)

6.9 g of potassium carbonate are added at ca. 25° C. to the solution of21.7 g of valsartan in 150 ml of acetone and 20 ml of water. Afterstirring for 2 hours at ca. 25° C., an almost clear solution isobtained, which is concentrated in a vacuum at ca. 50° C. bathtemperature. 55 ml of acetone are added to the residue (29.3 g) whichcontains residual water, and at ca. 35° C., over the course of ca. twohours, a total of 250 ml of tert.-butylmethylether is dispensed in.After stirring at ca. 25° C., the easily stirrable crystal suspension iscooled to 10° C., stirred for at least one hour, filtered by suction andwashed with 20 ml of tert.butylmethylether. The moist filter cake isdried over night at ca. 30 mbar and at 30° C. A colourless, slightlyhygroscopic crystal powder is obtained.

Elementary analysis: C₂₄H₂₇N₅O₃K₂, 3.42 mols H₂O % found % calculated C50.37 50.28 H 5.87 5.95 N 12.24 12.22 O 17.92 water 10.76 10.75 K 13.413.64

X-ray diffraction diagram measured with the diffractometer Scintag Inc.,Cupertino, Calif. 95014, US using a CuKα radiation.

Reflection lines and intensities of the most important lines of thehydrate of the di-potassium salt of valsartan, values given in 2θ in °:2θ in ° Intensity 4.9 strong 9.4 strong 11.4 weak 12.8 weak 14.0 weak15.0 weak 15.6 weak 16.6 medium 18.0 weak 18.5 weak 18.9 weak 20.7 weak21.5 weak 22.0 weak 22.7 medium 23.3 weak 24.1 medium 25.6 weak 25.8weak 27.1 medium 29.4 weakPreferred are hydrates comprising medium and strong intensity peaks.

EXAMPLE 13 Valsartan Calcium/Magnesium Mixed Salt

21.5 g of valsartan in 200 ml of isopropanol and 100 ml of water arestirred for ca. 3 hours at ca. 25° C. with 1.5 g of magnesium hydroxideand 1.9 g of calcium hydroxide. The practically clear solution isconcentrated in a vacuum at ca. 50° C. A total of 240 ml of ethylacetate is added with stirring to the still warm, semi-solid residuewhich contains residual water. Upon stirring over night at ca. 25° C.,initially sticky constituents are transformed into a homogeneoussuspension. The suspension is filtered by suction and washed with 20 mlof ethyl acetate. The moist filter cake is dried in a vacuum at 30-40°C. A colourless crystal powder is obtained.

The X-ray diffraction diagram corresponds to a conglomerate of calciumtetrahydrate and magnesium hexahydrate from example 1 and 2.

EXAMPLE 14 Valsartan bis-diethylammonium Salt

1.5 g of diethylamine are added dropwise at ca. 25° C. to the solutionof 4.35 g of valsartan in 60 ml of acetone. After a short time,crystallisation slowly sets in. After stirring over night, thecrystallisate is filtered by suction at ca. 20° C., washed with coldacetone and dried in a vacuum at ca. 50° C. A colourless crystal powderis obtained.

Elementary analysis. C₃₂H₅₁N₇O₃, 0.1 mols H₂O % found % calculated C65.82 65.84 H 8.90 8.84 N 16.84 16.80 O 8.52 water 0.34 0.34

X-ray diffraction diagram (reflection lines and intensities of the mostimportant lines) of the crystalline bis-diethylammonium salt 2θIntensity 4.7 weak 8.5 strong 9.3 strong 10.8 strong 11.3 weak 13.4strong 14.0 medium 14.3 weak 14.9 medium 17.1 medium 17.4 medium 17.6medium 18.3 weak 19.0 medium 20.0 weak 21.2 medium 21.6 weak 22.4 medium22.7 weak 24.9 medium 25.2 weak 27.0 weak

EXAMPLE 15 Valsartan bis-dipropylammonium Salt

2.1 g of dipropylamine are added dropwise at 25° C. to the solution of4.35 g of valsartan in 60 ml of acetone. When crystallisation has setin, the temperature is raised for a brief period to 40° C. and isallowed to drop to room temperature over ca. 2 hours. After stirringover night, the crystallisate is filtered by suction, washed twice with15 ml of acetone and dried in a vacuum at ca. 40° C. Granular crystalsare obtained.

Elementary analysis: C₃₆H₆₉N₇O₃, 0.05 mols H₂O % found % calculated C67.74 67.69 H 9.32 9.33 N 15.36 15.35 O 7.64 water 0.13 0.14

X-ray diffraction diagram (reflection lines and intensities of the mostimportant lines) of the crystalline bis-dipropylammonium salt 2θIntensity 8.5 strong 8.9 weak 9.4 strong 10.0 medium 11.2 weak 11.6 weak12.5 weak 13.2 strong 13.9 strong 14.3 weak 14.7 weak 15.1 weak 15.6weak 16.0 weak 17.0 medium 17.9 medium 18.7 strong 19.9 weak 20.4 weak20.6 weak 21.0 strong 21.7 weak 22.3 medium 23.1 strong 24.5 weak 25.5medium 25.8 weak 26.7 weak 28.6 weak

EXAMPLE 16 Bis-dibutylammonium Salt of Valsartan

A solution of 2.15 g of valsartan in 30 ml of acetone is mixed with 1.4g of dibutylamine at ca. 25° C. Crystallisation sets in after a shorttime, and the thick suspension is gradually diluted with 20 ml ofisopropyl acetate over ca. 1 hour. After stirring for 4 hours at ca. 25°C., the crystals are removed by suction, washed twice with 10 ml ofisopropyl acetate and dried in a vacuum at 50° C. A colourless, slightlyhygroscopic crystal powder is obtained.

Elementary analysis: C₄₀H₆₇N₇O₃, 0.5 mols H₂O % found % calculated C68.25 68.30 H 9.79 9.75 N 13.89 13.94 O 8.01 water 1.33 1.33

X-ray diffraction diagram (reflection lines and intensities of the mostimportant lines) of the crystalline bis-dibutylammonium salt 2θIntensity 7.5 very strong 8.5 medium 9.7 strong 12.7 strong 13.3 weak14.1 strong 15.1 medium 16.4 strong 17.7 weak 18.2 weak 19.5 strong 19.9medium 20.5 medium 21.4 medium 21.9 medium 22.2 medium 22.6 medium 23.0strong 23.7 weak 24.2 weak 24.7 medium 25.7 medium 26.0 weak 26.5 weak28.8 weak

FORMULATION EXAMPLE 1 Directly Compressed Tablet

proportion proportion per per tablet core No. Ingredient batch [g] [mg]1 valsartan calcium salt tetrahydrate 134.24 80 2 Avicel PH 102(microcrystalline 60.408 36 cellulose) 3 lactose (crystalline) 96.149457.3 4 crospovidone 7.551 4.5 5 aerosil 200 (silica, colloidal 0.839 0.5anhydrous) 6 magnesium stearate (vegetable) 6.2086 3.7

Ingredient no. 1 is sieved through a 0.5 mm sieve and mixed for 15minutes in a Turbula with ingredients 1-6. Tablets are compress using asingle punch tablet press with punches of a diameter of 8 mm.

FORMULATION EXAMPLE 2 Tablet Produced by Roller Corn Paction

proportion proportion per per tablet No. Ingredient batch [g] core[mg] 1valsartan magnesium salt hexahydrate 400 80 2 Avicel PH 102(microcrystalline 270 54 cellulose) 3 crospovidone 75 15 4 aerosil 200(silica, colloidal anhydrous) 7.5 1.5 5 magnesium stearate 15 3 6magnesium stearate 7.5 1.5

Ingredients no. 1-5 are mixed for 50 minutes and compacted on a Freundroller corn pactor. The band is milled and after admixing ingredient no6, compressed into tablets using a single punch tablet press withpunches of a diameter of 8 mm.

1. A calcium salt of valsartan.
 2. A salt according to claim 1 incrystalline, partially crystalline or amorphous form.
 3. Thetetrahydrate of the calcium salt of valsartan according to claim
 1. 4.The tetrahydrate according to claim 3, characterised by (i) an X-raypowder pattern taken with a Guinier camera comprising the followinginterlattice plane intervals: d in [Å]: 16.1±0.3, 9.9±0.2, 9.4±0.2,7.03±0.1, 6.50±0.1, 5.87±0.05, 5.74±0.05, 4.95±0.05, 4.73±0.05,4.33±0.05, 4.15±0.05, 4.12±0.05, 3.95±0.05; or (ii) an ATR-IR spectrumhaving the following absorption bands expressed in reciprocal wavenumbers (cm⁻¹): 1621 (st); 1578 (m); 1458 (m); 1441 (m); 1417 (m); 1364(m); 1012 (m); 758 (m); 738 (m); 696 (m); 666 (m).
 5. A salt accordingto claim 1 in the form of a solvate.
 6. A salt according to claim 1 inthe form of a hydrate.
 7. A salt according to claim 1 in a form selectedfrom the group consisting of (i) a crystalline form; (ii) a partlycrystalline form; (iii) an amorphous form; and (iv) a polymorphous form.8. A pharmaceutical composition comprising a compound according to claim1 and a pharmaceutically acceptable excipient or additive.
 9. Apharmaceutical composition according to claim 8, containing a saltaccording to claim 1 in combination with at least one compositionselected from the group consisting of a: (i) HMG-Co-A reductaseinhibitor or a pharmaceutically acceptable salt thereof, (ii)angiotensin converting enzyme (ACE) Inhibitor or a pharmaceuticallyacceptable salt thereof, (iii) calcium channel blocker or apharmaceutically acceptable salt thereof, (iv) aldosterone synthaseinhibitor or a pharmaceutically acceptable salt thereof, (v) aldosteroneantagonist or a pharmaceutically acceptable salt thereof, (vi) dualangiotensin converting enzyme/neutral endopeptidase (ACE/NEP) inhibitoror a pharmaceutically acceptable salt thereof, (vii) endothelinantagonist or a pharmaceutically acceptable salt thereof, (viii) renininhibitor or a pharmaceutically acceptable salt thereof, and (ix)diuretic or a pharmaceutically acceptable salt thereof.
 10. A method forthe treatment of diseases and conditions which can be inhibited byblocking the AT₁ receptor comprising administering a therapeuticallyeffective amount of the compound of claim 1 to a patient on needthereof.